19-40849290-G-C

Variant names:

• chr19-40849290-G-C
• rs7250713
• NM_000762.6:c.344-527C>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.344-527C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 150,198 control chromosomes in the GnomAD database, including 20,294 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 0.50 (20294 hom., cov: 28)
• Consequence: CYP2A6 NM_000762.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.843
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000762.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A6	NM_000762.6	MANE Select	c.344-527C>G		intron	N/A	NP_000753.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A6	ENST00000301141.10	TSL:1 MANE Select	c.344-527C>G		intron	N/A	ENSP00000301141.4
	CYP2A6	ENST00000596719.5	TSL:1	n.195-527C>G		intron	N/A
	CYP2A6	ENST00000600495.1	TSL:1	n.*156-527C>G		intron	N/A	ENSP00000472905.1

Frequencies

GnomAD3 genomes AF: 0.499 AC: 74893 AN: 150088 Hom.: 20275 Cov.: 28

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.493

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.499 AC: 74935 AN: 150198 Hom.: 20294 Cov.: 28 AF XY: 0.504 AC XY: 36878 AN XY: 73228

African (AFR) AF: 0.304 AC: 12393 AN: 40760

American (AMR) AF: 0.589 AC: 8954 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1914 AN: 3452

East Asian (EAS) AF: 0.550 AC: 2610 AN: 4744

South Asian (SAS) AF: 0.533 AC: 2499 AN: 4688

European-Finnish (FIN) AF: 0.640 AC: 6646 AN: 10384

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.564 AC: 38183 AN: 67682

Other (OTH) AF: 0.493 AC: 1031 AN: 2090

Alfa AF: 0.528 Hom.: 2793

Bravo AF: 0.489

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.61
PhyloP100		-0.84
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: rs7250713; hg19: chr19-41355195;