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The cytochrome P450 2D6 (  CYP 2D6 ) gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the   CYP 2D6  genotype‐phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next‐generation sequencing data. Using  CYP 2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increasing from 36% and 31%, respectively, when diplotypes did not incorporate structural variation. We also investigated whether the revised Clinical Pharmacogenetics Implementation Consortium ( CPIC ) recommendations for translating genotype to phenotype improve  CYP 2D6 activity predictions over the current system. Although the revised recommendations do not improve the correlation between activity score and  CYP 2D6 activity, perhaps because of low frequency of the   CYP 2D6*10  allele, the correlation with metabolizer phenotype group was significantly improved for both substrates. We also measured the function of seven rare coding variants: one (A449D) exhibited decreased (44%) and another (R474Q) increased (127%) activity compared with reference  CYP 2D6.1 protein. Allele‐specific analysis found that A449D is part of a novel   CYP 2D6*4  suballele,   CYP 2D6*4.028 . The novel haplotype containing R474Q was designated   CYP   2D6*138  by PharmVar; another novel haplotype containing R365H was designated   CYP 2D6*139 . Accuracy of  CYP 2D6 phenotype prediction is improved when the   CYP 2D6  gene locus is interrogated using next‐generation sequencing coupled with structural variation analysis. Additionally, revised  CPIC  genotype to phenotype translation recommendations provides an improvement in assigning  CYP 2D6 activity.

Interrogation of CYP 2D6 Structural Variant Alleles Improves the Correlation Between CYP 2D6 Genotype and CYP 2D6‐Mediated Metabolic Activity