19-40850376-T-C

Variant names:

• chr19-40850376-T-C
• rs1137115
• NM_000762.6:c.51A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000762.6(CYP2A6):​c.51A>G​(p.Val17Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,609,596 control chromosomes in the GnomAD database, including 456,122 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.76 (44365 hom., cov: 31)
  • Exomes 𝑓: 0.74 (411757 hom.)
• Consequence: CYP2A6 NM_000762.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 55 publications found

Genes affected

CYP2A6 (HGNC:2610): (cytochrome P450 family 2 subfamily A member 6) 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]

CYP2A6 Gene-Disease associations (from GenCC):

• coumarin resistance

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• nicotine dependence

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000268797 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.51A>G	p.Val17Val	synonymous_variant	Exon 1 of 9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.51A>G	p.Val17Val	synonymous_variant	Exon 1 of 9	1	NM_000762.6	ENSP00000301141.4
CYP2A6	ENST00000596719.5	n.65A>G		non_coding_transcript_exon_variant	Exon 1 of 6	1
CYP2A6	ENST00000600495.1	n.51A>G		non_coding_transcript_exon_variant	Exon 1 of 6	1		ENSP00000472905.1
ENSG00000268797	ENST00000601627.1	n.118-41615T>C		intron_variant	Intron 1 of 3	3		ENSP00000469533.1

Frequencies

GnomAD3 genomes AF: 0.760 AC: 114470 AN: 150552 Hom.: 44326 Cov.: 31

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.739

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.740

GnomAD2 exomes AF: 0.755 AC: 189110 AN: 250430 AF XY: 0.747

Gnomad AFR exome AF: 0.775

Gnomad AMR exome AF: 0.816

Gnomad ASJ exome AF: 0.743

Gnomad EAS exome AF: 0.777

Gnomad FIN exome AF: 0.843

Gnomad NFE exome AF: 0.745

Gnomad OTH exome AF: 0.737

GnomAD4 exome AF: 0.743 AC: 1083821 AN: 1458930 Hom.: 411757 Cov.: 74 AF XY: 0.740 AC XY: 536953 AN XY: 725792

African (AFR) AF: 0.774 AC: 25872 AN: 33442

American (AMR) AF: 0.815 AC: 36380 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19633 AN: 26114

East Asian (EAS) AF: 0.804 AC: 30874 AN: 38414

South Asian (SAS) AF: 0.645 AC: 55490 AN: 86030

European-Finnish (FIN) AF: 0.838 AC: 44652 AN: 53314

Middle Eastern (MID) AF: 0.676 AC: 3893 AN: 5758

European-Non Finnish (NFE) AF: 0.740 AC: 822602 AN: 1110978

Other (OTH) AF: 0.738 AC: 44425 AN: 60218

GnomAD4 genome AF: 0.760 AC: 114554 AN: 150666 Hom.: 44365 Cov.: 31 AF XY: 0.760 AC XY: 55886 AN XY: 73494

African (AFR) AF: 0.768 AC: 31574 AN: 41088

American (AMR) AF: 0.759 AC: 11498 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 2585 AN: 3458

East Asian (EAS) AF: 0.780 AC: 3809 AN: 4884

South Asian (SAS) AF: 0.657 AC: 3109 AN: 4734

European-Finnish (FIN) AF: 0.849 AC: 8842 AN: 10412

Middle Eastern (MID) AF: 0.726 AC: 212 AN: 292

European-Non Finnish (NFE) AF: 0.750 AC: 50738 AN: 67664

Other (OTH) AF: 0.737 AC: 1533 AN: 2080

Alfa AF: 0.753 Hom.: 15664

Bravo AF: 0.758

Asia WGS AF: 0.721 AC: 2470 AN: 3428

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.71
DANN	Benign	0.58
PhyloP100		-1.1
PromoterAI		-0.0075	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1137115; hg19: chr19-41356281; COSMIC: COSV56536887;