Simple ClinVar: an interactive web server to explore and retrieve gene and disease variants aggregated in ClinVar database

Abstract

Clinical genetic testing has exponentially expanded in recent years, leading to an overwhelming amount of patient variants with high variability in pathogenicity and heterogeneous phenotypes. A large part of the variant level data is aggregated in public databases such as ClinVar. However, the ability to explore this rich resource and answer general questions such as 'How many genes inside ClinVar are associated with a specific disease? or 'In which part of the protein are patient variants located?' is limited and requires advanced bioinformatics processing. Here, we present Simple ClinVar (http://simple-clinvar.broadinstitute.org/) a web server application that is able to provide variant, gene and disease level summary statistics based on the entire ClinVar database in a dynamic and user-friendly web-interface. Overall, our web application is able to interactively answer basic questions regarding genetic variation and its known relationships to disease. By typing a disease term of interest, the user can identify in seconds the genes and phenotypes most frequently reported to ClinVar. Subsets of variants can then be further explored, filtered or mapped and visualized in the corresponding protein sequences. Our website will follow ClinVar monthly releases and provide easy access to ClinVar resources to a broader audience including basic and clinical scientists.

Figure 1.

Simple ClinVar internal workflow and main module. (A) Information flow overview of the Simple ClinVar web application. The ClinVar database is pre-filtered with the clinvar.pre-filtering.pl script available at our GitHub page (http://github.com/dlal-group/Simple-ClinVar) to generate the ClinVar prefiltered file that is interrogated by the user. Upon query submission, the user interface generated with R software connects with pre-filtered file and UniProt features to deliver a result. (B) Simple ClinVar front page where the user can perform different types of queries.

Figure 2.

Simple ClinVar results section according to the three types of input supported. Examples of Simple ClinVar outputs according to (A) Database-wise query, (B) Gene-wise query and (C) Disease-term-wise query. The user can dynamically change between variant view (green, A), gene view (red, B), phenotype view (orange, C) and the table view (gray). For gene view, variants positions are shown according to the corresponding protein sequence. Here, if the user place the cursor over a variant a tooltip will appear with summary information (orange rectangle). Genetic variants are colored in green for synonymous, gray for missense, and red for protein truncating variants (Frameshift, small indels and stops gained).

Figure 3.

Dynamic filtering examples. (A) Gene view of the Disease-term-wise query for ‘epilepsy’ shows all genes associated before (upper panel) and after (bottom panel) filtering for pathogenic variants (left panel). (B) Gene view of the gene-wise query ‘SCN2A’ shows the genetic variants mapped on the protein sequence before (upper panel) and after (bottom panel) filtering for pathogenic and missense variants (on the left).