CYP2C9, CYP2C19, and CYP2D6 core alleles

We recently blogged about the use of PharmVar core alleles as the basis for the PharmGKB/CPIC CYP2D6, CYP2C19, and CYP2C9 allele definition tables, which are available as part of the gene-specific information tables. In addition to the core variant(s), the definition includes ambiguous nucleotides to reflect variation present in some suballeles of an allele which are also core variants of other alleles. The allele definitions are now used by the PharmGKB database for all annotations for these 3 genes.

CYP2D6 example:
CYP2D6 100C>T (P34S) is part of some but not all CYP2D6*4 suballeles. Therefore, it is not present in the CYP2D6*4 core allele. However, 100 C>T is part of core allele definitions of a number of CYP2D6 star alleles such as CYP2D6*10.
To reflect the possible presence of 100C>T in the *4 allele, the variant is represented as a “R” using IUPAC nucleotide code. "R" reflects that either a “G” or “A” (positive strand) can be present at the 100C>T position in *4. This is shown on the PharmGKB CYP2D6*4 overview page, which lists 100C>T positions and others next to the *4 key splicing variant 1847G>A (rs3892097).

CYP2C19 example:
For CYP2C19*1, the genomic reference sequence at position GRCh38 NC_000010.11:g.94842866 (rs3758581) is "A", which is present in CYP2C19*1.001(*1A), however all other *1 suballeles have a "G" (I331V) at this position. All suballeles of a star (*) are assumed to have similar functional status. The I331V is prominent in CYP2C19 and part of many alleles.  To reflect the possibility of either base at this position, the NC_000010.11:g.94842866 position is included as "R" for the CYP2C19*1 allele at PharmGKB.

For more information about cytochrome P450 star alleles and suballeles, see PharmVar .

PharmGKB has been updated to contain annotations on main star alleles such as *2, *3, etc. and not individual suballeles. If a publication specifically mentions a suballele, this association will be annotated on the main star allele and the suballele will be mentioned in the annotation notes.