Copy Number Variant Grid¶
This page provides the ability to:
- Sort variants by Tier
- Review the copy number variants identified by DRAGEN CNV
- Review additional annotations and linkouts to external resources for each variant (see CNV Grid Guide below for further details)
CNV grid guide¶
The order of columns in the CNV grid can be changed using the column headers. This will reset to default upon navigating away from the page or on page refresh. 20 variants are shown by default, and more are loaded dynamically when scrolling to the bottom of the page.
Please use the below key in conjunction with the below sections to learn more about the columns in the variant grid.
Key
| # | Section | Description |
|---|---|---|
| 1 | Actions | A Classify button which can be clicked to open the classification drawer, and changes to display the classification of the variant once it has been assigned (for further details see the recording interpretation page) |
| 2 | Tier | This can be Tier A, Tier B, Tier Null, or "-" for untiered variants or variants that do not fall within a gene. For further details, please visit the Tier section below. |
| 3 | Genomic region / Cytoband | The genomic region and cytoband of the variants, with a button which displays a linkout to IGV (for read depth investigation). There is also a button that opens a menu containing further links to external databases and resources (DECIPHER (browser), gnomAD CNV, gnomAD SV, UCSC and DGV) for the variant, and a button to copy the variant coordinates in Alamut format |
| 4 | Size (bp) | Length of the copy number variant in base pairs |
| 5 | Type / Copy number | The type of the copy number variant. Loss (deletion CNV) or Gain (duplication CNV). The copy number state is indicated by the number in brackets next to the type |
| 6 | Genes | HGNC gene symbol(s) which the variant affects. We show the first four affected genes (additional genes are indicated wi/th a "+n" pill, with n being the number of genes). Clicking on any gene pill (or +n pill) will open the gene overlay (multi-gene overlay by default). For further details, please visit the genes section below. |
| 7 | Gene colour and exon overlap | Genes in Tiered variants are coloured green according to their PanelApp green gene status. For further details, please visit the genes section below. The E symbol in the gene pill represents that the CNV has exonic overlap with at least one transcript for that gene. If that transcript is also a MANE transcript (MANE Select or MANE Plus Clinical), then we also see a M symbol next to the E. Some genes will display a warning icon, as there is currently a bug in CellBase which affects the exon overlap annotations for some CNVs |
| 8 | Protein coding genes | The number of genes that the CNV overlaps with that have at least one transcript with a protein coding biotype |
| 9 | OMIM associated diseases | Count of associated diseases for the gene in OMIM. For further details, please visit the OMIM section below. |
| 10 | Regions | PanelApp ISCA regions the CNV overlaps. The region pill is coloured green according to its PanelApp green gene status. For further details, please visit the regions section below. |
| 11 | Allele frequency (Loss only) | Frequency track - Displays the percentage of individuals in a reference dataset who carry a copy loss CNV that reciprocally overlaps the query CNV. Reciprocal overlap - Calculated based on CNVs that overlap the query CNV by at least 50% in both directions. These columns will only be populated where the CNV is a copy loss variant - for copy gain variants, a - will be visible. |
| 12 | Individuals with CNV (Gain only) | Frequency track - Displays the percentage of indivduals in a reference dataset who carry a copy gain CNV that reciprocally overlaps the query CNV. Reciprocal overlap - Calculated based on CNVs that overlap the query CNV by at least 50% in both directions. These columns will only be populated where the CNV is a copy gain variant - for copy loss variants, a - will be visible. |
Sorting¶
By default, all variants are sorted by Tier ascending and by variant coordinates. Variants can be sorted by Tier ascending or descending by using the arrow icon or menu in the column headers.
Tier¶
This can be Tier A, Tier B, Tier Null, or "-" for untiered variants or variants that do not fall within a gene. When clicking on the tooltip next to the Tier, the Tier overlay opens.
For details on how to sort by Tier, please visit the sorting section.
Tier overlay¶
The Tier overlay displays details about the Genomics England Tiering outcome for the variant.
The highest Tier assigned to the variant and the clinical indication for the proband are displayed at the top of the overlay.
Below this we see all prioritisation results (previously known as Report Events) for the variant displayed in a table; the gene, panel, and the variant segregation, inheritance and penetrance considered by Tiering as part of the finding are displayed per prioritisation result.
Key
| # | Section | Description |
|---|---|---|
| 1 | Highest Tier | The highest Tier assigned to the variant by Genomics England Rare Disease Tiering |
| 2 | Clinical indication | The clinical indication for the proband |
| 3 | Tier | Tier assigned by Genomics England Rare Disease Tiering |
| 4 | Entity | Gene or region contained within the CNV for the Genomics England Rare Disease Tiering result |
| 5 | Entity colour | The entity pill is coloured green when the entity is green in at least one PanelApp panel (/superpanel) of the most recent version at the time of case ingestion, where that panel is also a panel that has been applied to the case |
| 6 | GMS panel name | Name of the GMS panel applied to the patient that is associated with the Genomics England Rare Disease Tiering result, with a link to the GMS signed off PanelApp panel |
| 7 | Links to GEL Rare Disease Genome Analysis Guide | Links to the relevant pages in the Genomics England Rare Disease Genome Analysis Guide |
Genes¶
HGNC gene symbol(s) which the variant affects; affected genes are displayed in the grid. This is different to the behaviour in the SNV grid - here we display the first 4 genes, with a +n pill to represent the number of further genes affected by the CNV. Those that are green in a PanelApp panel are displayed first.
Clicking on the gene, or +n in the Genes column opens the gene overlay.
Gene colour¶
If any of the further genes represented by the +n pill are also green in a PanelApp panel, then the +n pill will also be displayed green.
Multi gene overlay¶
The multi-gene overlay contains the key information for each gene affected by the CNV, in a single table. More detailed information for each individual gene is accessible in the single gene overlay.
Key
| # | Section | Description |
|---|---|---|
| 1 | Total number of genes | Total number of genes that the CNV overlaps |
| 2 | Variant coordinates | Coordinates for the CNV |
| 3 | Gene name / header | The gene names can be seen along the top of the overlay - these are clickable, with each tab displaying the relevant information for that gene. |
| 4 | Gene colour | The gene pill is coloured green when the gene is green in at least one PanelApp panel of the most recent version at the time of case ingestion. |
| 5 | Exon overlap | E symbol in the gene pill represents that the CNV has exonic overlap with at least one transcript for that gene. If that transcript is also a MANE transcript (MANE Select or MANE Plus Clinical), then we also see a M symbol next to the E. Some genes will display a warning icon, as there is currently a bug in CellBase which affects the exon overlap annotations for some CNVs |
| 6 | Gene | HGNC gene symbol which the variant affects. Gene is coloured according to PanelApp green gene status in the same way as the gene symbols in the header |
| 7 | PanelApp panels | PanelApp panels for the gene (including version and a link-out to the PanelApp page for the panel). If the gene is present in no PanelApp panels, then a - is displayed. A maximum of 2 PanelApp panels are displayed in the grid. If the gene is in any further PanelApp panels, the number of additional panels is denoted by +n. |
| 8 | Impacted exons (MANE) | Displays the exons that are overlapped by the CNV for any MANE transcripts for that gene. A M or M+ icon will be displayed next to the exon overlap to denote whether the transcript is MANE Select or MANE Plus Clinical. If no exons are overlapped in MANE transcripts, a - will be displayed. Some MANE transcripts will display Not available instead of the exon overlap, as there is currently a bug in CellBase which affects the exon overlap annotations for some genes |
| 9 | OMIM associated diseases | Displays any diseases associated with the gene in OMIM, and a link-out to the OMIM page for each disease. A maximum of 2 associated diseases are displayed in the grid. If the gene is associated with more than 2 diseases in OMIM, the number of additional diseases is denoted by +n. |
| 10 | Protein coding | Denotes whether the gene is protein coding (i.e. has any transcript with a biotype that is protein coding) |
| 11 | Links | Linkouts to external resources and databases for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER) |
Single gene overlay¶
The gene overlay which displays relevant information for the gene.
This includes Ensembl IDs for the gene and transcripts, PanelApp panels the gene is present in, OMIM associated diseases for the gene, the c. HGVS nomenclature for the CDS change, the p. HGVS nomenclature for the protein change, and links to external resources for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER). All variants are annotated with PanelApp panels, with the data used for annotation being updated every hour (data is static once the case is ingested into the New IB).
The gene names can be seen along the top of the overlay; a variant can be associated with more than one gene. Gene names are clickable, with each page displaying the relevant information for that gene.
Key
| # | Section | Description |
|---|---|---|
| 1 | Gene name / header | The gene names can be seen along the top of the overlay; a variant can be associated with more than one gene. These are clickable, with each tab displaying the relevant information for that gene. |
| 2 | Gene colour | The gene pill is coloured green when the gene is green in at least one PanelApp panel of the most recent version at the time of case ingestion. |
| 3 | Exon overlap | E symbol in the gene pill represents that the CNV has exonic overlap with at least one transcript for that gene. If that transcript is also a MANE transcript (MANE Select or MANE Plus Clinical), then we also see a M symbol next to the E. Some genes will display a warning icon, as there is currently a bug in CellBase which affects the exon overlap annotations for some CNVs |
| 4 | Gene ID | Ensembl gene ID |
| 5 | Links | Linkouts to external resources and databases for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER) |
| 6 | PanelApp panels | This section displays the PanelApp panels for the gene (including version and a link-out to the PanelApp page for the panel). For each panel, we see the gene rating (green, amber, red), and PanelApp's MOI for the gene. If there is no MOI recorded in PanelApp, then this will be displayed as Unknown. If the gene has been removed from the panel in the most recent version at the time of case ingestion, then a '-' is displayed in the Gene status column, and the Gene MOI will be displayed as Unknown. If the gene is present in no PanelApp panels, then None is displayed in place of all data. |
| 7 | OMIM associated diseases | Displays any diseases associated with the gene in OMIM, as well as the gene-phenotype mode of inheritance, and a link-out to the OMIM page for each disease. Where there is more than 1 associated disease the data is displayed in a table, and pages of the table can be navigated between using the arrow buttons. |
| 8 | Transcript information | Table containing details of transcripts for that gene which overlap the variant. A '-' in the table indicates that this data is not available for the transcript. Transcripts are ordered by the following priority: MANE Select, MANE Plus Clinical. Any transcripts that do not match these criteria are displayed unordered. |
| 9 | Transcript / RefSeq Match | Ensembl transcript ID is provided for each transcript, and RefSeq NM number is provided for MANE transcripts. These provide linkouts to the respective transcript pages. RefSeq transcript IDs are only provided for MANE transcripts, as only these guarantee 100% sequence identity between the respective Ensembl and Refseq transcript IDs. If the transcript is MANE then a flag will be displayed (M for MANE Select and M+ for MANE Plus Clinical). If more than 5 transcripts exist, then these can be navigated through using the arrows at the bottom of the table |
| 10 | Exon overlap | The specific exons in that transcript that are overlapped by the CNV. Some exons will display Not available as there is currently a bug in CellBase which affects the exon overlap annotations for some CNVs |
| 11 | Impacted region | The region of the transcript that is impacted by the CNV: Full transcript, Partial coding sequence, Partial non-coding sequence, Not applicable |
| 12 | Transcript biotype | Indicates the type of transcript; this can indicate whether it is coding or non-coding and its role |
| 13 | Protein ID (Ensembl ID) | Ensembl ID for the protein produced by the transcript |
OMIM associated diseases¶
There is a count of associated diseases in OMIM for each gene visible in the row for the variant.
Clicking the i icon opens the OMIM overlay. Different from the SNV grid, the OMIM overlay in the CNV grid displays all gene-disease associations for the variant, across all genes associated with the variant.
OMIM data that is used for annotating variants will be updated at least every quarter.
OMIM overlay¶
The OMIM overlay displays each disease associated with any gene in OMIM that is associated with the variant, the gene-phenotype mode of inheritance, and a link-out to the OMIM page for each disease (N.B. this is different to the SNV overlay where the associations are displayed for a single gene only). If there is no mode of inheritance in OMIM for an associated disease then Unknown will be visible. The pages of the table can be navigated between using the arrow buttons. The associated diseases are ordered with those associated with a green gene coming first, and then ordered alphabetically by associated disease name.
Where a disease is associated with multiple genes for that variant, multiple genes will be displayed next to that disease in the Gene column.
Regions¶
PanelApp ISCA regions the CNV overlaps. Where the CNV does not overlap a region, a - is displayed.
Region colour¶
The region pill is coloured green when the region is green in at least one PanelApp panel of the most recent version at the time of case ingestion.
Region overlay¶
The region overlay which displays relevant information for the region. This includes the ISCA region name, the required percentage of overlap, PanelApp panels the region is present in, and Haploinsufficiency or Triplosensitivity Score, as well as link-outs to PanelApp and ClinGen for the region. The data used for PanelApp panel annotation is updated every hour (data is static once the case is ingested into the New IB).
There is a region overlay per region - if the CNV overlaps multiple regions, the overlay for one would need to be closed in order to view the overlay for the other.
Key
| # | Section | Description |
|---|---|---|
| 1 | Region name / header | The descriptive, cytogenetic name for the region can be seen along the top of the overlay. A variant can be associated with more than one region, but to see information for a second region the overlay should be exited and the other region name clicked on. |
| 2 | Region colour | The gene pill is coloured green when the gene is green in at least one PanelApp panel of the most recent version at the time of case ingestion. |
| 3 | Region coordinates | Coordinates for the region |
| 4 | ClinGen ISCA region ID | ClinGen curated identifier for the region |
| 5 | Required percentage overlap | The minimum percentage of the defined genomic region that needs to be covered by a CNV for it to be considered clinically significant |
| 6 | Links | Linkouts to external resources and databases for the region (PanelApp and ClinGen) |
| 7 | PanelApp panels | This section displays the PanelApp panels for the region (including version and a link-out to the PanelApp page for the panel). For each panel, we see the region status (green, amber, red), and PanelApp's MOI for the region. If there is no MOI recorded in PanelApp, then this will be displayed as Unknown. If the region has been removed from the panel in the most recent version at the time of case ingestion, then a '-' is displayed in the Region status column, and the Region MOI will be displayed as Unknown |
| 8 | Haploinsufficiency / triplosensitivity score | The score for the region, as provided by PanelApp. Possible options for haploinsufficiency are: 3 (Sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype) or 30 (Gene associated with autosomal recessive phenotype). Possible options for triplosensitivity are: 2 (Emerging evidence suggesting dosage sensitivity is associated with clinical phenotype), 3 (Sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype). |
Abbreviations
| Abbreviation | Definition |
|---|---|
| ACGS | Association for Clinical Genomic Science |
| ACMG | American College of Medical Genetics and Genomics |
| CDS | Coding DNA Sequence |
| CNV | Copy Number Variant |
| CVA | Clinical Variant Ark |
| New IB | New Interpretation Browser |
| GEL | Genomics England |
| GMS | Genomic Medicine Service |
| GLH | Genomic Laboratory Hub |
| HGVS | Human Genome Variation Society |
| HTML | Hyper Text Markup Language |
| HSCN | Health and Social Care Network (N3) |
| IGV | Integrative Genomics Viewer |
| IP | Interpretation Portal |
| NGIS | National Genomics Informatics System |
| PID | Patient Identifiable Data |
| QC | Quality Control |
| SO | Sequence Ontology |
| SNV | Single Nucleotide Variant |
| SV | Structural Variant |
| TOMS | Test Order Management Service |
| UAT | User Acceptance Testing |
| VCF | Variant Call Format File |
| WGS | Whole Genome Sequencing |