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 comprehensively aggregated in public databases such as ClinVar and are publicly accessible. However, the ability to explore this rich resource and answer general questions such as “How many missense variants are associated to a specific disease or gene?” 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 their known relationships to disease. Our website will follow ClinVar monthly releases and provide easy access to the rich ClinVar resource to a broader audience including basic and clinical scientists.
Simple ClinVar web server pre-filtering stage and R source code of http://simple-clinvar.broadinstitute.org/
Input: download ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/tab_delimited/variant_summary.txt.gz and decompress
Run: $perl clinvar.pre-filtering.pl variant_summary.txt
The program performs the following taks:
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First, we keep only entries from the human reference genome version GRCh37.p13/hg19 and referring to canonical transcripts.
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Second, Molecular consequence is inferred through the analysis of the Human Genome Variation Society (HGVS) sequence variant nomenclature field. HGVS format contains string patterns that allow molecular consequence inference (e.g. ENST00001234 c.3281 [p.Gly1046Arg]). Specifically, when the variant is reported to cause an amino acid change different to the reference it is annotated as a “missense” variant (e.g. p.Gly1046Arg). If the genetic variant leads to the same amino acid (e.g. p.Gly1046Gly) or a stop codon (e.g. p.Gly1046*) the entry is annotated as “synonymous” or “stop-gain” variant, respectively. Depending on the observed outcome, small insertions and deletions molecular consequence (collectively “indels”; e.g. p.Gly1046Glyfs., p.Gly1046Glyins., p.Gly1046del.*) are separated in to “frameshifts” and “in-frame indels”.
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Third, we reduced the complexity of the clinical significance field by regrouping and merging them in to five unique and non-redundant categories: “Pathogenic”, “Likely pathogenic”, “Risk factor and Association”, “Protective/Likely benign” and “Benign”. Conflicting interpretations of pathogenicity, variants of unknown significance (VUS) and contradictory evidence (e.g. “Likely benign” alongside “Risk” evidences) were combined together in to an “Uncertain/Conflicting” category. Similarly, variants annotated with multiple evidence categories of the same evidence direction such as “Pathogenic” alongside “Likely pathogenic” were combined and the respective lower evidence category assigned. Fourth, ClinVar entries with phenotypes annotated as “not provided” and “not specified” were combined in to one single category called “Not provided / Not specified”.
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Fourth, ClinVar entries with missing annotations such as the absence of anHGVS variant name or incomplete genomic coordinates are filtered out. By the time of submission 493,240 out of 503,065 (98.04%) ClinVar entries (April 22 release) are included in Simple ClinVar.
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Output: clinvar.[month.of.release].pf that serves as an input for the Simple ClinVar web server hosted at http://simple-clinvar.broadinstitute.org/
User interface: ui.R
Server code: server.R
Input1: clinvar.[month.of.release].pf
Input2: genes.refSeq
Input3: gene-ccds-seq-length-uniprot.txt
Usage:
Step 1: place on the same folder Input1, Input2, Input3, ui.R and server.R
Step 2: on R studio run server.R or ui