19-40850376-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000762.6(CYP2A6):c.51A>G(p.Val17=) 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 19-40850376-T-C is Benign according to our data. Variant chr19-40850376-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CYP2A6	NM_000762.6	c.51A>G	p.Val17=	synonymous_variant	1/9	ENST00000301141.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2A6	ENST00000301141.10	c.51A>G	p.Val17=	synonymous_variant	1/9	1	NM_000762.6	P1
CYP2A6	ENST00000596719.5	n.65A>G		non_coding_transcript_exon_variant	1/6	1
CYP2A6	ENST00000600495.1	c.51A>G	p.Val17=	synonymous_variant, NMD_transcript_variant	1/6	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

GnomAD3 exomes AF: 0.755 AC: 189110 AN: 250430 Hom.: 73388 AF XY: 0.747 AC XY: 101112 AN XY: 135348

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 SAS exome AF: 0.645

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

Gnomad4 AFR exome AF: 0.774

Gnomad4 AMR exome AF: 0.815

Gnomad4 ASJ exome AF: 0.752

Gnomad4 EAS exome AF: 0.804

Gnomad4 SAS exome AF: 0.645

Gnomad4 FIN exome AF: 0.838

Gnomad4 NFE exome AF: 0.740

Gnomad4 OTH exome AF: 0.738

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

Gnomad4 AFR AF: 0.768

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.748

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.849

Gnomad4 NFE AF: 0.750

Gnomad4 OTH AF: 0.737

Alfa AF: 0.752 Hom.: 15446

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

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

Publications

LitVar

Other links and lift over

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