Germline CNV Grid

Features

• Review the germline copy number variants identified by the cancer pipeline for cases ingested after 6.12.0 release and associated annotations
• Apply certain filters (e.g. copy number)
• Search for specific variants within a certain chromosome, region or gene
• View Ensembl or RefSeq transcript identifiers
• Sort the list of variants (e.g. by tier, genomic coordinate, copy number, or size)
• Flag a variant for further review
• Add or remove a variant from the GTAB summary
• Add a comment and assign an ACGS classification to a variant
• Report whether the variant has been tested by another method i.e., Standard of Care Testing
• Report whether a variant is likely to be an artefact or a true variant

Variant Grid GuideSearchingSortingFilteringAdvanced FilteringVariant InterpretationAdding Variants to the GTAB summaryPage Errors

An overview of the Variant Grid is shown in the following table

Key

#	Section	Description
1	Information Alerts	Relevant disclaimers and alerts will be shown here in a dropwdown.
2	Search	Search for variants within specific genomic regions, chromosomes or genes. Details on how to search can be found in the "Searching" tab.
3	Filters	Add or remove filters applied to the variant grid. By default, the variant grid will be filtered to display variants in genes belonging to Tier 1 and Tier 3.
4	Actions	Actions including: flagging variants, adding comments, and adding or removing variants from the GTAB summary. The Actions buttons are present for each variant and the action selected only applies to the variant you are interacting with.
5	Tier and gene	Tier and HGNC gene symbol(s) which the variant affects. We show the affected genes in the highest tier.
6	GRCh38 coordinates	Coordinates of the variant. Clicking the IGV icon will show the variant in IGV.
7	Chromosomal bands	The chromosomal band(s) overlapping this variant.
8	Variant type / Copy number	Variant type for this CNV: Gain, Loss, or copy neutral loss of heterozygosity (LOH). Followed by copy number.
9	Size (KB)	Size of the CNV in kilobases.
10	Confidence / Support	CNVs will have a confidence value assigned to indicate whether the call is High or Low confidence. For Dragen calls, "High" and "Low" indicate high and low confidence variants corresponding to PASS variants and all other variants, respectively.
11	VCF filter	Shows whether the variant has passed the pipeline filters. For variants that haven’t passed, the reason is shown in red.
12	QC flag	Flags that indicate a variant call may be of a lower quality and at greater risk of being a false positive. Hover over the QC flag for a description.
13	Population frequencies (AF/AUC)	Two different methods are used to calculate allele frequencies for CNVs: reciprocal overlap using an 80% threshold (AF) and area under the curve (AUC). See the Cancer Genome Analysis Guide for more information about each method. CNV frequencies were calculated using 5,415 germline samples from unrelated individuals (participants in the Cancer program of the 100,000 Genomes Project and the COVID-19 research project).
14	Classification	The assigned ACGS tiering of a variant. Please refer to the Variant Interpretation section for more information.

Tip: Open the transcript overlay

On your variant of interest, click any of the HGNC gene symbols shown under the Tier / Gene column (section 5 of the Variant grid guide) to open the transcript overlay (example shown below).

You can use the search bar to search for variants by:

• Gene symbol e.g., "TP53"
• Coordinates (chromsome, start coordinate and end coordinate) e.g., "17:7660779-7688538"
• Chromosome e.g., "17"

Searching

Searching will filter the variant grid to variants that match the search terms. If no variants are returned, there may be no variants in the chromosome, region or gene specified.

By default, all variants are sorted by Tier ascending and by variant coordinates. Variants can be sorted by Tier, GRCH38 coordinates, copy number or size ascending or descending by using the arrow icon or menu in the column headers. When sorting is applied to a column, the arrow icon will appear next to the column title in the direction of the sort (ascending = up, descending = down).

To change the sorting of the variant grid from Domain to GRCH38 coordinates, follow these steps:

• Click the arrow icon on the column header to sort the grid by GRCH38 coordinates in ascending or descending order
• Click the three dots on the column header and select 'Sort by Coordinates ASC' or 'Sort by Coordinates DESC'
• To reset the variant grid to the default sorting order (by Tier) click the three dots on the column header and select 'Reset to default'

Sorting

Only one sort can be activated at the time. By default, the first 10 variants are shown, sorted by tier and coordinates. To see the remaining variants, scroll to the bottom of the page and new variants will continue to load.

Germline CN Variant Filters

• Tier
• VCF filter
• Flag status
• Copy Number

By default, the variant grid is filtered by Tier 1 and 3.

Applying filters

1. Click the '+' symbol next to 'Add filter'
2. Chose your filter of interest from the dropdown menu and click the '+' symbol
3. Click on the arrow dropdown and select your filter options e.g., Mode of Action, Oncogene. The variant grid will update accordingly

Removing filters

1. Individual filters can be removed by clicking the 'x' symbol next to the filter
2. Default filtering settings can be restored by clicking the 'Reset' button above the filter toolbar
3. Multi-select filters can be reset by selecting 'Clear'
   

Counts

The count on the top left shows the number of variants remaining after filters have been applied. The total number is the number of variants the pipeline identified before any quality checks have been applied.

Applying Multiple Filters

For information on applying multiple filters please see the "Advanced Filtering" section

We support applying multiple filters to the variant grid at the same time. The filters we currently support for germline CNVs can be applied at the variant level. In future, we may support gene level filters for CNVs.

Filter	Level
Tier	Variant
Flag status	Variant
VCF filter	Variant
Copy Number	Variant

• When applying multiple filters at the same level, the filters are exclusive (See example 1 and example 2)

#	Filter 1	Filter 2	Result
1	Tier 1	Flag status: Flagged	Tier 1 variants that are 'Flagged'
2	Tier 3	Copy Number: 0	Any Tier 3 variant with a copy number of 0

You can add interpretations and comments corresponding to a variant in the variant grid using the Interpretation drawer.

To open the Interpretation drawer:

1. On your variant of interest, click Classify/Edit Classification (icon shown below)

2. The Interpretation drawer will open on the right of the screen

   

Tip

Please refer to the following GTAB-related section to know how to add a germline CNV and its interpretation to the GTAB summary.

Variant QualityClassifyingValidationActionabilityComments

Artefact AssessmentArtefact Reasons

Artefact Assessment

To indicate whether the variant is likely to be a technical artefact or a true variant:

1. Select one option from the Artefact assessment dropdown list.
2. The selection will automatically save and the Saved icon will appear once saved.
3. All changes will be stored in the Interpretation drawer history.

Info

If a variant has been marked as a likely artefact in step 1, please refer to the Artefact reasons section.

Artefact Reasons and Artefact Comments

If a variant has been marked as a likely artefact, the Interpretation drawer will display an additional field: Artefact reasons. To indicate the reason why the variant is likely to be a technical artefact:

1. Select one or multiple options from the Artefact reasons dropdown list.
2. The selection will automatically save and the Save icon will appear once saved.
3. Type a comment in the Artefact comment text box to support the options selected in the previous step and click Save comment.
4. All changes will be stored in the Interpretation drawer history.

Warning

Updating the artefact assessment to "True variant" will remove the artefact reasons and comment data from the Interpretation drawer but it will still be available in the Interpretation drawer history.

Tip

Please refer to the Comments section to know how to edit and delete previous artefact comments.

Classifying

To view or add classifications:

1. Select one option from the ACGS classification dropdown list.
2. The selection will automatically save and the Save icon will appear once saved.
3. All changes will be stored in the Interpretation drawer history.

ValidationAssay Type

Validation

To indicate whether the variant has been validated:

1. Select one option from the Has this variant or entity been tested by another method (either prior to or following receipt of this WGA)? dropdown list.
2. The selection will automatically save and the Saved icon will appear once saved.
3. All changes will be stored in the Interpretation drawer history.

Info

If in step 1 you indicated that the variant has been validated by another method (prior or post WGA), please refer to the Assay Type section.

Assay Type and Assay Comment

If the variant has been validated by another method, the Interpretation drawer will display an additional field: Assay type. To select which assay type(s) the variant has also been detected in:

1. Select one or multiple options from the Assay type dropdown list.
2. The selection will automatically save and the Save icon will appear once saved.
3. Type a comment in the Assay comment text box to support the options selected in the previous step and click Save comment.
4. All changes will be stored in the Interpretation drawer history.

Warning

Updating the validation to any of the "No" options will remove the assay type and comment data from the Interpretation drawer but it will still be available in the Interpretation drawer history.

Tip

Please refer to the Comments section to know how to edit and delete previous assay comments.

Select Actionability Options and Add Actionability and Usability Comments

To enter the type of potential actionability associated with a variant and add actionability and usability comments:

1. Select one or multiple options from the Type of (potential) actionability dropdown list.
2. The selection will automatically save and the Saved icon will appear once saved.
3. Type a comment in the Actionability comment text box to support the actionability options selected in the previous step and click Save comment.
4. Select one option from the How has/will this potentially actionable variant or entity been/be used? dropdown list.
5. The selection will automatically save and the Saved icon will appear once saved.
6. Type a comment in the Usability comment text box to support the options selected in the previous step and click Save comment.
7. All changes will be stored in the Interpretation drawer history.

Tip

Please refer to the Comments section to know how to edit and delete previous actionability and usability comments.

Add Artefact, Assay, Actionability, Usability or Analysis Comments

To add an artefact, assay, actionability, usability, or analysis comment to any variant:

1. Type your comment in the Artefact, Assay, Actionability, Usability, or Analysis comment text box.
2. Click Save comment.
3. The comment is added to the corresponding section together with the name of the user who added the comment and a date-timestamp to indicate when the comment was added to the variant.
4. Only the last comment will be seen under the corresponding text box. Previous comments can be seen in the Interpretation drawer history.

Info

The Artefact comment text box only appears after selecting the "Likely artefact" option from the Artefact assessment dropdown list.

The Assay comment text box only appears after selecting any of the "Yes" options (validated prior or post WGA) from the Has this variant or entity been tested by another method (either prior to or following receipt of this WGA)? dropdown list.

The Actionability comment text box only appears after selecting one option from the Type of (potential) actionability dropdown list.

The Usability comment text box only appears after selecting one option from the How has/will this potentially actionable variant or entity been/be used? dropdown list.

Edit Previous Artefact, Assay, Actionability, Usability or Analysis Comments

To edit a previous artefact, assay, actionability, usability, or analysis comment:

1. On your comment of interest, click the icon next to the date-timestamp (icon shown below).
2. Click Edit.
3. Make your changes to the previous comment.
4. Click Save comment.

Note

You can only edit your own comments.

Delete Previous Artefact, Assay, Actionability, Usability or Analysis Comments

To delete a previous artefact, assay, actionability, usability, or analysis comment:

1. On your comment of interest, click the icon next to the date-timestamp (icon shown below).
2. Click Delete.
3. In the confirmation pop-up message that appears, click Delete.

Note

You can only delete your own comments.

You can add any germline CNV and its interpretation to the GTAB summary from the variant grid or interpretation drawer.

To add a germline CNV to the GTAB summary:

1. On your variant of interest, click Add to GTAB report (icon shown below) from the variant grid or Interpretation drawer
2. Go to the GTAB summary. In the navigation sidebar, click GTAB report (icon shown below).

Info

At the moment, it is only possible to add variants one by one to the GTAB summary. Please refer to the GTAB summary section for more details.

When we fail to load the gene data needed for search and gene filters to work, you won’t be able to apply any gene list filters or search by gene. All other information on the page will still be available. When we fail to load all variant data, we will show a full page error. In both cases try reloading the page.