Whether you're using the SEARCH application to look up a single structural variant, or you're analyzing a case with CNVs from your MY CASES tab, you're likely to end up in the Variant Interpretation hub for a deletion or a duplication. In this article, you'll find an overview of the segment interpretation tools provided by Franklin.
The Variant Interpretation hub:
How to get to the Variant Interpretation hub
There are two different ways to get to the Variant Interpretation hub for a certain variant:
From the SEARCH application, enter the variant details and click Search. It will take you directly to the Variant Interpretation page.
Franklin supports different nomenclatures, and you can check out the examples provided to find which one you prefer.
In addition, some optional questions will pop up, encouraging you to include case details and phenotypic information that might be relevant for the variant interpretation.
From the MY CASES application. If you have a structural variant in the workbench or variant list of your case, you can click on the tile to expand it and then select Full detail view or click on the cytobands to open the Variant Interpretation page.
ACMG/ClinGen Automated Classification
Franklin's AI-based algorithm provides an automated CNV classification based on the latest ACMG/ClinGen guidelines, leveraging evidence from a wide array of publicly available data sources and dedicated resources for structural variants curated by our team of cytogenetic specialists. If you'd like to know more about how Franklin computes this automated pathogenicity classification, check out this article.
In the Franklin ACMG Classification tab, you can find not only the overall classification result, but also the explanation for each rule that was met or unmet, and their corresponding score. To get more information about each specific criteria, you should click on the See Details button.
Franklin's classification engine will suggest a classification according to the latest guidelines. However, if you wish to modify the classification, feel free to click on the Edit button below the score of each rule. This will open a pop-up window where you can toggle between Met and Unmet for the criteria, and also adjust the points assigned to that piece of evidence.
Variant Assessment
The variant assessment tab presents a wide range of tools and visualizations that should help you analyze the clinical relevance of the variant.
Clinical Summary
This section shows the automated ACMG classification along with the most relevant genes and regions in the CNV, based on Haploinsufficiency and Triplosensitivity evidence (by Clingen and Franklin).
The most relevant syndromes will be presented, and phenotypes that match the syndrome will be highlighted.
Region Viewer
Region viewer displays the genomic region information. This is a dynamic view where you can click on a cytoband and have all the relevant information:
The entire Chromosome is shown with the detailed cytobands, the borders of the CNV will be highlighted with red lines on the chromosome.
Genes in region. In large region genes details are displayed after zoom-in
Dosage sensitivity
case CNV |(sample variant)
Curated Submissions: all the Clinvar and Decipher submissions, each line is colored by the submitted classification. A set of filters can help view variants similar to yours, for example you can filter by “Deletion” or “Duplication” and also set the “Overlap” percentage.
The SV region viewer also allows filtering options and track selection.
Confidence (case analysis only)
Each confidence level reflects the likelihood that the CNV is real, helping users assess the reliability of the call. The confidence section visualises 3 parameters that can help assess the cnv confidence: depth, predicted copy number, and prediction scores. For more information regarding the CNV confidence view and assessment go to CNV detection by Franklin
Internal Occurrence
This widget displays variants with significant overlap specifically from your own organization's clinical data repository. If you'd like to know more, click on See details to further information and even access the previous case.
Clinical Evidence
Clinical evidence dysplays detailed curated submissions from Clinvar, Decipher and also from Franklin community, including classification, phenotypes, % overlap, submitter, etc. each tile is expanded and includes also linkouts to the source.
Alternate Reference
The alternate reference is available for further assessment if needed, including a direct link to the variant assessment tab for the alternate allele.
Genes and Regions
The 'Genes and Regions' tab will provide comprehensive information about the genes and regions associated with the Copy Number Variation (CNV).
This list of genes and regions can be filtered by:
Type: Coding/Non-coding gene, region
Impact: Whole gene, exonic, intronic, etc.
Sensitivity: Evidence of Hapoinsufficiency/Triplosensitivity
Inheritance: Autosomal recessive/dominant, X-linked, Y-linked, etc.
Condition source: Monarch, OMIM, Ophanet, etc.
Genes: Each of the genes affected by the CN
If available, ClinGen Haploinsufficiency or Triplosensitivity information will be shown for each tile, along with relevant links. Additionally, the calculated LOF score, Decipher HI score, pLI, and o/e LOF (upper) will be provided. It's important to note that while Clingen LOF score information may not always be available, Franklin calculates the loss of function score based on the number of reported Pathogenic/Likely pathogenic null variants in a gene. A gene with 5 or more null P/LP reported variants is considered to have strong evidence of LOF as a disease mechanism, 2-4 variants are considered to have moderate evidence, and a single variant is considered to have limited evidence
For each gene, the corresponding associated condition(s) will be displayed on the tile, showcasing the phenotypes that match the case. In the case of large CNV variants, Gene filtration and Sorting can be utilized to streamline the process
More information about the genes and region tab click here.
Associated Conditions
The Associated Conditions tab will present the list of conditions that may be caused by the queried variant. Using complex algorithms, and an abundance of annotated data for each variant from sources such as OMIM, Orphanet, GeneReviews, Diseases, and PubMed Franklin calculates and aggregates gene-disease correlations.
Each condition is represented by a tile, showing the condition name, the sources for the correlation evidence, the disease inheritance model, and the strength of the evidence linking the condition to the gene, as well as the matching phenotypes for the case.
By clicking on the arrow on the right, or anywhere in the tile, you can access the Condition page, where you find a brief summary of the disease, alongside all the phenotypes reported to be associated with the disease, and their occasionality (if available). Franklin will also link the condition entry to all well-known databases, such as OMIM, GENCC and Orphanet.
Publications
The Publications tab is powered by Franklin's powerful Natural Language Processing (NLP) AI-based algorithm. Here, the platform constantly examines large volumes of genomic literature and highlights the most relevant evidence for the specific case.
The dedicated search engine annotates publications based on genes, conditions, phenotypes, and specific variants, and provides a prioritized list of relevant publications based on biomarkers and phenotypic information. Users can filter the list according to a specific gene of interest and the date of publication.
If you'd like to learn more about this tool, head to Franklin's Publications engine article.
My Organization Assessments
Under this last tab, you can get insights from your organization's knowledge base. Here you are able to find the previous curated classifications of similar structural variants within your Franklin organization, alongside their interpretation text.
Still have questions? Reach out to our Support Team, they'll be happy to help!