CYP2D6 Structural Variants: Deletions, Duplications and Gene Fusions Explained

The *5 allele is a deletion of the entire CYP2D6 gene. Someone with *1/*5 has one working copy instead of two, which CPIC scores as an intermediate metabolizer, and *4/*5 has no working copy at all, a poor metabolizer.^[3] In a VCF, a deletion on one chromosome usually looks like ordinary homozygous calls on the other, so *1/*5 is easily read as *1/*1. Poor and intermediate metabolizers get less pain relief from codeine and tramadol, because those drugs need CYP2D6 to become active, and can build up higher levels of drugs that CYP2D6 clears, such as some tricyclic antidepressants.^[5][6]

A duplicated working copy (for example *1x2 or *2x2) adds its activity to the total. Someone with *1/*1x2 has three working copies, which CPIC scores as an ultrarapid metabolizer.^[3] Ultrarapid metabolizers turn codeine and tramadol into their active forms too quickly, which CPIC links to a risk of serious side effects, and they can clear some antidepressants so fast that a standard dose doesn't work.^[5][7] Duplications of a non-working copy (such as *4x2) change nothing, which is why the copy that is duplicated matters too. How common duplications are varies widely by ancestry.^[4]

CYP2D6 sits next to two similar genes, CYP2D7 and CYP2D8, and the region rearranges. Some chromosomes carry a hybrid that is partly CYP2D6 and partly CYP2D7. *36 is one: it has no function and often travels with a reduced-function *10 copy as the tandem *36+*10, common in people of East Asian ancestry. *68 is another, often seen as *68+*4.^[2][1] A VCF can show the *10 variants without showing that a *36 copy sits beside them, which is usually harmless for the score but can mislead in other combinations.

A VCF lists the places where your DNA differs from the reference genome. A missing or extra copy of a whole gene isn't a difference at any single position, so it doesn't appear. The BAM (or CRAM) file your sequencing provider made before the VCF holds every read aligned to the genome. Counting reads over CYP2D6, and comparing them with regions of the genome that are reliably present in two copies, shows how many copies you carry; reads that match CYP2D7 in part show fusions. Clinical labs measure this with dedicated assays because chips and standard variant calls can't.^[8]

Gene2Rx's CYP2D6 Structural Analysis reads the CYP2D6 region and the comparison regions from your BAM or CRAM file, aligned to GRCh37 or GRCh38, and calls the full CYP2D6 result: which alleles you carry, how many copies, and any fusion, including *5 deletions, duplications and the *36 and *68 hybrids. Every result comes with its confidence, and when your reads fit the best result less clearly than most, you also see the next most likely result and which of your medications it would change. Your report is then regenerated from your VCF on file.

CYP2D6 structure matters most if you take, or may be prescribed, a drug that CYP2D6 handles: codeine, tramadol or hydrocodone for pain, a tricyclic antidepressant, paroxetine, atomoxetine, metoprolol, ondansetron or tamoxifen.^[5][6] If you already have whole genome sequencing, you likely have the data to measure it. If your only data is from a consumer chip, CYP2D6 structural variants can't be seen in it, and a clinical CYP2D6 test is the way to find out. Either way, talk to your prescriber before changing how you take any medication.

Changes in the shape of the CYP2D6 gene rather than single letters in it. Most people have two copies, one on each chromosome 22, but a chromosome can carry none (the *5 deletion), two or more (a duplication, written x2, x3), or a copy fused with the neighboring CYP2D7 gene, such as *36 or *68.

No. Both list variants at specific positions, and a missing, extra or fused copy of a whole gene isn't a variant at any one position. Finding them needs the aligned reads (a BAM or CRAM file from whole genome sequencing) or a clinical CYP2D6 assay.

Many whole genome services let you download the aligned reads, as a BAM or CRAM file with an index, alongside the VCF. Check your provider's downloads page. Gene2Rx reads BAM and CRAM files aligned to GRCh37 or GRCh38.

No. Your browser reads the file's index, checks it has enough data, takes only the parts covering CYP2D6 and the few dozen short regions it is compared against, a tiny fraction of your genome, and uploads those. The rest of the file stays on your computer.

Each result shows how confident the call is, and when a call is less certain you see the next most likely result and the medications it would change. Before you pay, your browser checks that your file has enough data for a reliable call, and a file that doesn't is turned away.

$10 added to a whole genome report at checkout, or $10 later from your account page. A Full Report from a whole genome VCF with CYP2D6 Structural Analysis is $80 in all.