rs6413474

Variant names:

• chr19-40843854-T-C
• rs6413474
• NM_000762.6:c.1427A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000762.6(CYP2A6):​c.1427A>G​(p.Lys476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,611,382 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (21 hom., cov: 30)
  • Exomes 𝑓: 0.013 (135 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.402
• Publications: 17 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036874413).
• BS2: High Homozygotes in GnomAd4 at 21 Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A6	NM_000762.6	MANE Select	c.1427A>G	p.Lys476Arg	missense	Exon 9 of 9	NP_000753.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A6	ENST00000301141.10	TSL:1 MANE Select	c.1427A>G	p.Lys476Arg	missense	Exon 9 of 9	ENSP00000301141.4	P11509
	ENSG00000268797	ENST00000601627.1	TSL:3	n.117+42439T>C		intron	N/A	ENSP00000469533.1	M0QY20
	CYP2A6	ENST00000874215.1		c.1517A>G	p.Lys506Arg	missense	Exon 9 of 9	ENSP00000544274.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1575 AN: 150708 Hom.: 21 Cov.: 30

Gnomad AFR AF: 0.00313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00702

Gnomad ASJ AF: 0.0324

Gnomad EAS AF: 0.000608

Gnomad SAS AF: 0.0142

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0140

GnomAD2 exomes AF: 0.0122 AC: 3055 AN: 250690 AF XY: 0.0134

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0132 AC: 19269 AN: 1460556 Hom.: 135 Cov.: 33 AF XY: 0.0135 AC XY: 9832 AN XY: 726606

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00197 AC: 66 AN: 33452

American (AMR) AF: 0.00512 AC: 229 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 764 AN: 26100

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39108

South Asian (SAS) AF: 0.0202 AC: 1737 AN: 86146

European-Finnish (FIN) AF: 0.0237 AC: 1265 AN: 53404

Middle Eastern (MID) AF: 0.00920 AC: 53 AN: 5762

European-Non Finnish (NFE) AF: 0.0129 AC: 14383 AN: 1111572

Other (OTH) AF: 0.0128 AC: 770 AN: 60300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0104 AC: 1575 AN: 150826 Hom.: 21 Cov.: 30 AF XY: 0.0111 AC XY: 820 AN XY: 73608

African (AFR) AF: 0.00312 AC: 128 AN: 41076

American (AMR) AF: 0.00701 AC: 106 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 112 AN: 3462

East Asian (EAS) AF: 0.000610 AC: 3 AN: 4922

South Asian (SAS) AF: 0.0143 AC: 67 AN: 4700

European-Finnish (FIN) AF: 0.0256 AC: 267 AN: 10442

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 860 AN: 67820

Other (OTH) AF: 0.0139 AC: 29 AN: 2086

Alfa AF: 0.0119 Hom.: 3

Bravo AF: 0.00855

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0115 AC: 1401

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.86
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.90	T
PhyloP100		-0.40
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.025
Sift	Benign	0.50	T
Sift4G	Benign	0.53	T
Vest4		0.037
MPC		1.6
ClinPred		0.0012	T
GERP RS		0.73
gMVP		0.37
Mutation Taster		=97/3	polymorphism

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: rs6413474; hg19: chr19-41349759;