Abstracts

Rationale: Clinical genetic testing for epilepsies and other related neurodevelopmental disorders has exponentially expanded in recent years. The genetic information generated and accumulated in databases such as ClinVar can be overwhelming and difficult to assess for people without prior bioinformatic knowledge. We have previously developed the Simple-ClinVar web server to explore and retrieve gene and disease information aggregated in ClinVar database in a friendly platform. Specifically, the Simple ClinVar user can quickly answer questions such as “How many missense variants are associated to a specific disease or gene?” or “In which part of the protein are patient's variants located?” Here, we present Simple ClinVar v2 which includes additional features oriented to improve the experience of users in the clinical field and connect with external resources for variant interpretation. Methods: We designed the new version of Simple ClinVar based on internal objectives as well as the accumulated comments and suggestions from active users. The whole ClinVar database is retrieved directly from the ClinVar ftp site (ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/) on a monthly basis. Annotation, interactive summary statistics, visualization, and variant mapping was developed with the Shiny framework of Rstudio software. App deployment, hosting, and update is performed with Google Cloud services. Results: Simple ClinVar v2 retains original output design. For example, the query “epilepsy” will yield 6,239 genetic variants with missense SNVs (n= 2,865) as the most common type (ClinVar entries version May 2019). A total of 150 genes related to epilepsy are shown in ascending order with SCN1A (n=516), SCN9A (n=486) and CACNA1H (n=433) as the three most recurrent. However if the user filters for pathogenic variants, the top ten gene list is updated to SCN1A (n=263), DEPDC5 (n=71), GRIN2A (n=27). The user can quickly conclude that the most frequently mutated genes and the genes with the most pathogenic variants are not the same. Similarly, the query “SCN1A” indicates that 30% of missense variants are classified as of uncertain significance (VUS, n=533), widely distributed across the protein and associated with 29 disorders. Simple ClinVar v2 now includes visualization of large scale variants such as copy number variants and small insertions and deletions in a genomic context. ClinVar information is connected to the genome aggregation database (gnomAD) which can help the user answer the question: 'has been my variant observed in the general population?'. Furthermore, we integrated variant interpretation scores to variant reports (e.g. CADD, Polyphen, SIFT). Finally, Simple ClinVar v2 now includes a submission feature that allows the user to map their own variants on top of ClinVar and gnomAD reports. Conclusions: Simple ClinVar v2 is able to interactively answer basic questions regarding genetic variation and their known relationships to disease. The present release of our web server now connects ClinVar reports to external resources that further complements variant analysis. The user can identify in seconds the most important clinically tested disease genes by typing just the disease term and can explore immediately where these variants are located. The tool is available online at simple-clinvar.broadinstitute.org for clinical use as well as for educational purposes. Funding: Eduardo Pérez-Palma was supported by Dravet Foundation research grant conceded to Dennis Lal