rs8192726

Variant names:

• chr19-40848591-C-A
• rs8192726
• NM_000762.6:c.493+23G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-40848591-C-A
• chr19-40848591-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000762.6(CYP2A6):​c.493+23G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0706 in 1,606,586 control chromosomes in the GnomAD database, including 6,116 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 0.074 (644 hom., cov: 31)
  • Exomes 𝑓: 0.070 (5472 hom.)
• Consequence: CYP2A6 NM_000762.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 36 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.493+23G>T		intron_variant	Intron 3 of 8	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.493+23G>T		intron_variant	Intron 3 of 8	1	NM_000762.6	ENSP00000301141.4
CYP2A6	ENST00000596719.5	n.344+23G>T		intron_variant	Intron 2 of 5	1
CYP2A6	ENST00000600495.1	n.*305+23G>T		intron_variant	Intron 3 of 5	1		ENSP00000472905.1
ENSG00000268797	ENST00000601627.1	n.118-43400C>A		intron_variant	Intron 1 of 3	3		ENSP00000469533.1

Frequencies

GnomAD3 genomes AF: 0.0742 AC: 11227 AN: 151376 Hom.: 642 Cov.: 31

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0693

GnomAD2 exomes AF: 0.0794 AC: 19611 AN: 247084 AF XY: 0.0817

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.0470

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.0989

Gnomad NFE exome AF: 0.0633

Gnomad OTH exome AF: 0.0698

GnomAD4 exome AF: 0.0702 AC: 102180 AN: 1455096 Hom.: 5472 Cov.: 52 AF XY: 0.0723 AC XY: 52268 AN XY: 722838

African (AFR) AF: 0.0775 AC: 2585 AN: 33356

American (AMR) AF: 0.0463 AC: 2065 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 1721 AN: 26006

East Asian (EAS) AF: 0.164 AC: 6256 AN: 38214

South Asian (SAS) AF: 0.126 AC: 10781 AN: 85858

European-Finnish (FIN) AF: 0.0997 AC: 5305 AN: 53214

Middle Eastern (MID) AF: 0.0583 AC: 334 AN: 5726

European-Non Finnish (NFE) AF: 0.0622 AC: 68936 AN: 1108182

Other (OTH) AF: 0.0700 AC: 4197 AN: 59986

GnomAD4 genome AF: 0.0741 AC: 11226 AN: 151490 Hom.: 644 Cov.: 31 AF XY: 0.0756 AC XY: 5596 AN XY: 73976

African (AFR) AF: 0.0786 AC: 3249 AN: 41312

American (AMR) AF: 0.0428 AC: 654 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.162 AC: 788 AN: 4866

South Asian (SAS) AF: 0.125 AC: 595 AN: 4766

European-Finnish (FIN) AF: 0.103 AC: 1083 AN: 10548

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0655 AC: 4450 AN: 67940

Other (OTH) AF: 0.0687 AC: 144 AN: 2096

Alfa AF: 0.0695 Hom.: 512

Bravo AF: 0.0686

Asia WGS AF: 0.104 AC: 359 AN: 3430

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.78
PhyloP100		-0.052
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs8192726; hg19: chr19-41354496; COSMIC: COSV56534383; COSMIC: COSV56534383;