rs56113850

Variant names:

• chr19-40847202-T-C
• rs56113850
• NM_000762.6:c.655-151A>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.655-151A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 1,201,092 control chromosomes in the GnomAD database, including 184,585 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 0.52 (21334 hom., cov: 31)
  • Exomes 𝑓: 0.55 (163251 hom.)
• Consequence: CYP2A6 NM_000762.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 89 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.655-151A>G		intron_variant	Intron 4 of 8	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.655-151A>G		intron_variant	Intron 4 of 8	1	NM_000762.6	ENSP00000301141.4
CYP2A6	ENST00000596719.5	n.506-151A>G		intron_variant	Intron 3 of 5	1
CYP2A6	ENST00000600495.1	n.*467-151A>G		intron_variant	Intron 4 of 5	1		ENSP00000472905.1
ENSG00000268797	ENST00000601627.1	n.118-44789T>C		intron_variant	Intron 1 of 3	3		ENSP00000469533.1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78260 AN: 151024 Hom.: 21327 Cov.: 31

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.526

GnomAD4 exome AF: 0.549 AC: 576353 AN: 1049954 Hom.: 163251 AF XY: 0.545 AC XY: 281459 AN XY: 516868

African (AFR) AF: 0.390 AC: 9090 AN: 23280

American (AMR) AF: 0.600 AC: 11478 AN: 19116

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 10063 AN: 17416

East Asian (EAS) AF: 0.303 AC: 9264 AN: 30624

South Asian (SAS) AF: 0.405 AC: 22513 AN: 55538

European-Finnish (FIN) AF: 0.559 AC: 23245 AN: 41598

Middle Eastern (MID) AF: 0.526 AC: 1631 AN: 3102

European-Non Finnish (NFE) AF: 0.571 AC: 464934 AN: 814260

Other (OTH) AF: 0.536 AC: 24135 AN: 45020

GnomAD4 genome AF: 0.518 AC: 78291 AN: 151138 Hom.: 21334 Cov.: 31 AF XY: 0.514 AC XY: 37894 AN XY: 73790

African (AFR) AF: 0.402 AC: 16533 AN: 41082

American (AMR) AF: 0.584 AC: 8900 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1992 AN: 3468

East Asian (EAS) AF: 0.325 AC: 1613 AN: 4964

South Asian (SAS) AF: 0.414 AC: 1972 AN: 4766

European-Finnish (FIN) AF: 0.568 AC: 5956 AN: 10486

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39440 AN: 67844

Other (OTH) AF: 0.525 AC: 1104 AN: 2104

Alfa AF: 0.467 Hom.: 5189

Bravo AF: 0.516

Asia WGS AF: 0.427 AC: 1465 AN: 3434

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.077
DANN	Benign	0.35
PhyloP100		-1.6
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: rs56113850; hg19: chr19-41353107; COSMIC: COSV56537913; COSMIC: COSV56537913;