CYP1A2

protein-coding

cytochrome P450 family 1 subfamily A member 2, the group of Cytochrome P450 family 1

Gene summary

This gene 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. The protein encoded by this gene localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include caffeine, aflatoxin B1, and acetaminophen. The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000761.5

Inheritance

ClinVar variants

U:47B:6

Top phenotype

CYP1A2-related drug metabolism

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr15:74,748,845-74,756,607

External References & Databases

Ensembl (ENSG00000140505)

Transcript & Mutation Effects

hg38 • Region Span ~7.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

CYP1A2-related drug metabolismAD

Manifestation: General

Intervention: Pharmacogenomic

Rationale: Variants may also be related to subclinical metabolism of a number of agents (including medications), as well as related as a susceptibility factor; Porphyria cutanea tarda, severity of refersto a susceptibility locus and/or evidence or clinical applicability unclear

Refs: 8035341; 10101295; 10233211; 10376760; 11153915; 12172216; 16522833; 17971810; 20881513; 20955109; 20147896; 19636338; 21121774; 19682433; 21989077

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP1A2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 48

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000761.5. 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				3 clinvar		3
missense			46 clinvar	2 clinvar	1 clinvar	49
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	47	5	1	53

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000761.5	RefSeq	NP_000752.2	6	MANE Select
ENST00000343932.5	Ensembl	ENSP00000342007.4	6	MANE Select
ENST00000872474.1	Ensembl	ENSP00000542533.1	5	Standard
ENST00000872474.2	Ensembl	ENSP00000542533.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Benzodiazepine Pathway, Pharmacokinetics
Tryptophan metabolism - Homo sapiens (human)
Retinol metabolism - Homo sapiens (human)
Steroid hormone biosynthesis - Homo sapiens (human)
Metabolism of xenobiotics by cytochrome P450 - Homo sapiens (human)

Biological Process

steroid catabolic process
porphyrin-containing compound metabolic process
xenobiotic metabolic process
toxin biosynthetic process
post-embryonic development

Molecular Function

monooxygenase activity
iron ion binding
electron transfer activity
oxidoreductase 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

endoplasmic reticulum membrane
organelle membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000343932
Coding exons: 6
Length: 7359
Individuals with no LoFs: 125592
Homozygous LoFs: 0
Heterozygous LoFs: 156
Defined: 125748
p: 0.000620

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.417	338	317	1.07	0.0000204	3372
Missense (PolyPhen)		112	106.13	1.0553		1201
Synonymous	-0.605	145	136	1.07	0.00000887	1076
Loss of Function	0.460	16	18.1	0.883	9.63e-7	191

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.0039	0.0039	notable
East Asian	0.0014	0.0014	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00048	0.00046	rare
South Asian	0.00079	0.00078	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen. Participates in the bioactivation of carcinogenic aromatic and heterocyclic amines. Catalizes the N-hydroxylation of heterocyclic amines and the O- deethylation of phenacetin. {ECO:0000269|PubMed:14725854}.;

Recessive Scores

pRec: 0.722

Intolerance Scores

LoFtool: 0.560
RVIS EVS: -0.6
RVIS percentile EVS: 18.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.783

Gene Damage Prediction

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