We have incorporated information from the PolyPhen method of predicting the effect of an amino acid substitution on the properties of the protein product (9–10). PolyPhen predictions for SNPs in dbSNP build 126 were downloaded from the PolyPhen web site (http://genetics.bwh.harvard.edu/pph/data; the PolyPhen 2 tool is now available at http://genetics.bwh.harvard.edu/pph2 but at the time of writing did not yet appear to provide a comprehensive set of predictions for download). When PolyPhen predictions are enabled by the user on the main page, the SNP/gene functional property will be replaced by the PolyPhen prediction when a prediction for that SNP exists. The prediction can be ‘benign’, ‘possibly damaging’ or ‘probably damaging’, and users may specify a different prioritization score for each prediction. By default, these are 1, 2 and 3, respectively, which correspond to the default values for intron, missense and frameshift, so that the PolyPhen prediction may increase or decrease the prioritization score compared to the default value of 2 for missense SNPs.
