Mendelian Clinically Applicable Pathogenicity (M-CAP) Score

M-CAP is the first pathogenicity classifier for rare missense variants in the human genome that is tuned to the high sensitivity required in the clinic (see Table). By combining previous pathogenicity scores (including SIFT, Polyphen-2 and CADD) with novel features and a powerful model, we attain the best classifier at all thresholds, reducing a typical genome rare (<1%) missense variant list from 300 to 120, while never mistaking 95% of known pathogenic variants as benign. Details can be found here.

For Clinicians: Use M-CAP scores to filter out patient variants of uncertain significance (VUS) with high confidence. M-CAP scores > 0.025 are considered to be possibly pathogenic and <= 0.025 are considered to be likely benign.

For Competitors: Please be sure to compare M-CAP and other methods with great care. Pathogenic and benign sets should both consist of only rare missense variants. M-CAP scores do not exist for common variants. It is common practice for clinicians to discard common variants as being likely benign. Also make sure that the test dataset you are using for the comparison is not used to train M-CAP or any of the other methods included in the comparison. This will lead to unrealistically optimistic results that do not generalize to novel pathogenic variants.

Method Authors' Recommended Pathogenicity threshold Misclassified known pathogenic variants
SIFT < 0.05 38%
Polyphen-2 > 0.8 31%
CADD > 20 26%
MetaLR > 0.5 27%
M-CAP > 0.025 5%

Score a variant

Enter the GRCh37/hg19 coordinate for a missense variant to retrieve its M-CAP score.
Convert from hgvs notation (i.e. AKT3 c.49G>A) to hg19 genomic coordinates (1:243859016) by entering in UCSC genome browser search box and copy pasting here.

GRCh37/hg19

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GRCh37/hg19.{{chrom}}:{{pos | number}} Gene {{gene}}
Reference Allele {{ref}}

Alt Mutation M-CAP 95% TPR
{{allele.alt}} rare, common, {{allele.mutationType}}* N/A {{allele.mcap | number:3}} Unscored Variant Likely Benign Possibly Pathogenic
M-CAP scores not available for any alleles at {{chrom}}:{{pos | number}} which is not a valid exome position.
M-CAP scores not available for some alleles at {{chrom}}:{{pos | number}}.
M-CAP scores only rare (≤ 1% allele frequency), missense variants based on the Ensembl build 75 gene set.
Multiple mutation types observed for some alleles at {{chrom}}:{{pos | number}}.
Alleles whose mutation type is marked with a star indicate that the mutation type for this mutation varies based on isoform. See FAQ section for more details on how we resolve such discrepances.

M-CAP scores on UCSC genome browser.

Access M-CAP scores on the UCSC genome browser here.

How to cite

Jagadeesh, K., Wenger, A., Berger, M., Guturu, H., Stenson, P., Cooper, D., Bernstein, J., and Bejerano, G. (2016). M-CAP eliminates a majority of variants with uncertain significance in clinical exomes at high sensitivity. Nature Genetics, 2016. DOI: 10.1038/ng.3703

Download M-CAP Scores

M-CAP source code

M-CAP public git repository can be found here.

Contact

Email mcap@cs.stanford.edu with any questions

Licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Please email for commercial licensing inquiries.