rs8192730

Variant names:

• chr19-40844677-C-G
• rs8192730
• NM_000762.6:c.1257G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000762.6(CYP2A6):​c.1257G>C​(p.Glu419Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,610,716 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0070 (31 hom., cov: 31)
  • Exomes 𝑓: 0.00057 (33 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92

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]

ENSG00000268797 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034837425).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00702 (1063/151482) while in subpopulation AFR AF= 0.0237 (977/41228). AF 95% confidence interval is 0.0225. There are 31 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1063 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.1257G>C	p.Glu419Asp	missense_variant	Exon 8 of 9	1	NM_000762.6	ENSP00000301141.4
ENSG00000268797	ENST00000601627.1	n.117+43262C>G		intron_variant	Intron 1 of 3	3		ENSP00000469533.1
CYP2A6	ENST00000599960.1	n.176G>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
CYP2A6	ENST00000596719.5	n.*245G>C		downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1063 AN: 151368 Hom.: 31 Cov.: 31

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00141

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00385

GnomAD3 exomes AF: 0.000822 AC: 206 AN: 250620 Hom.: 9 AF XY: 0.000583 AC XY: 79 AN XY: 135552

Gnomad AFR exome AF: 0.00989

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000331

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000574 AC: 838 AN: 1459234 Hom.: 33 Cov.: 32 AF XY: 0.000501 AC XY: 364 AN XY: 726026

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000911

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00702 AC: 1063 AN: 151482 Hom.: 31 Cov.: 31 AF XY: 0.00700 AC XY: 518 AN XY: 74006

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.00354

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00141

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.00182 Hom.: 3

Bravo AF: 0.00739

ExAC AF: 0.00210 AC: 255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.0
DANN	Benign	0.93
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.092
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Vest4		0.065
MutPred		0.20		Loss of methylation at K420 (P = 0.0922);
MVP		0.24
MPC		0.076
ClinPred		0.00079	T
GERP RS		-1.6
gMVP		0.25

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: rs8192730; hg19: chr19-41350582; COSMIC: COSV99040519; COSMIC: COSV99040519;