Use of computational tools to assess the functional impact of missense variants in the CYP2D6 gene

The CYP2D6 gene is highly functional. Responsible for encoding the enzyme CYP2D6, present in the cytochrome P450 family without oxidative system of drug metabolism, can metabolize about 60% of the drugs with hepatic passage, being responsible for absorption of the drug. Single Nucleotide Polymorphism (SNP) is a type of genetic polymorphism associated with nucleotide variation in the DNA molecule, and can be classified as: synonymous, non-synonymous (nsSNPs) and nonsense. Our hypothesis is that nsSNPs may cause significant effects on the CYP2D6 enzyme function. From the 330 nsSNPs currently available at NCBI's Variation Viewer database, we performed a functional impact analysis with a total of 16 computational tools. These tools were divided into 4 different groups according to their methodology: sequence homology (SIFT, Provean, Mutation Assessor, Panther) supervised learning (SNAP, PhD-SNP, SuSPect, MutPred) consensual methods (PredictSNP, PON- P2, Condel, Meta-SNP) and methods based on protein and structural sequence (SNPs3D, Site DirectedMutator (SDM), PoPMuSiC, PolyPhen2). After the analyzes, we classified the deleterious convergent nsSNPs as those classified as deleterious by at least three tools in each of the four groups. A total of 17 deleterious convergent nsSNPs were identified. These nsSNPs could have an impact in the functionality of the CYP2D6 enzyme.