CYP2A6

protein-coding

cytochrome P450 family 2 subfamily A member 6, the group of Cytochrome P450 family 2

Gene summary

This gene, CYP2A6, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by phenobarbital. The enzyme is known to hydroxylate coumarin, and also metabolizes nicotine, aflatoxin B1, nitrosamines, and some pharmaceuticals. Individuals with certain allelic variants are said to have a poor metabolizer phenotype, meaning they do not efficiently metabolize coumarin or nicotine. This gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. The gene was formerly referred to as CYP2A3; however, it has been renamed CYP2A6. [provided by RefSeq, Jul 2008]

Previous symbols:

CYP2A3

MANE transcript

NM_000762.6

Inheritance

ClinVar variants

U:67B:16

Top phenotype

CYP2A6-related drug metabolism

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr19:40,843,541-40,850,447

External References & Databases

Ensembl (ENSG00000255974)

Transcript & Mutation Effects

hg38 • Region Span ~6.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

coumarin resistanceNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007390

Submitter: Labcorp Genetics (formerly Invitae)

nicotine dependenceNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0008575

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

CYP2A6-related drug metabolismAD

Manifestation: General

Intervention: Pharmacogenomic

Rationale: Selection and dosing of medications may be affected by the presence of variants

Refs: 2322567; 9409631; 9827545; 10093988; 12042667; 12325023; 19238117; 23089672

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP2A6 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 71

not providedTotal: 10

Tegafur responseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000762.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	6 clinvar	2 clinvar	9
missense			65 clinvar	5 clinvar	2 clinvar	72
nonsense			1 clinvar			1
start loss						0
frameshift					1 clinvar	1
splice donor/acceptor (+/-2bp)						0
Total	0	0	67	11	5	83

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000762.6	RefSeq	NP_000753.3	9	MANE Select
ENST00000301141.10	Ensembl	ENSP00000301141.4	9	MANE Select
ENST00000600495.1	Ensembl	ENSP00000472905.1	2	Standard
ENST00000874213.1	Ensembl	ENSP00000544272.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Artemisinin and Derivatives Pathway, Pharmacokinetics
Retinol metabolism - Homo sapiens (human)
nicotine degradation III
Metabolism of xenobiotics by cytochrome P450 - Homo sapiens (human)
Drug metabolism - other enzymes - Homo sapiens (human)

Biological Process

organic acid metabolic process
xenobiotic metabolic process
steroid metabolic process
coumarin metabolic process
drug metabolic process

Molecular Function

iron ion binding
coumarin 7-hydroxylase activity
arachidonic acid epoxygenase activity
steroid hydroxylase activity
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen

Cellular Component

cytoplasm
endoplasmic reticulum membrane
cytoplasmic microtubule
organelle membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301141
Coding exons: 9
Length: 6910
Individuals with no LoFs: 125122
Homozygous LoFs: 12
Heterozygous LoFs: 466
Defined: 125600
p: 0.00190

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.53	375	300	1.25	0.0000173	3241
Missense (PolyPhen)		123	108.4	1.1346		1182
Synonymous	-3.39	162	116	1.40	0.00000659	940
Loss of Function	0.894	15	19.2	0.780	9.01e-7	226

Population LoF Frequency

Population	CAF	p-value	Status
African	0.024	0.023	notable
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0.00069	0.00069	rare
East Asian	0.0013	0.0013	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.00023	0.00023	rare
Other	0.00082	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4- cineole 2-exo-monooxygenase. Possesses low phenacetin O- deethylation activity. {ECO:0000269|PubMed:11695850, ECO:0000269|PubMed:16086027, ECO:0000269|PubMed:17125252, ECO:0000269|PubMed:18779312, ECO:0000269|PubMed:1889415, ECO:0000269|PubMed:1944238}.;

Recessive Scores

pRec: 0.521

Intolerance Scores

LoFtool: 0.916
RVIS EVS: 0.3
RVIS percentile EVS: 71.64

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.830

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium