rs28399454

Positions:

• chr19-40845362-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_000762.6(CYP2A6):​c.1093G>A​(p.Val365Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,611,520 control chromosomes in the GnomAD database, including 589 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.030 (309 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (280 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP5: Variant 19-40845362-C-T is Pathogenic according to our data. Variant chr19-40845362-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0038315356). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.1093G>A	p.Val365Met	missense_variant	7/9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.1093G>A	p.Val365Met	missense_variant	7/9	1	NM_000762.6	ENSP00000301141	P1
CYP2A6	ENST00000596719.5	n.944G>A		non_coding_transcript_exon_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4477 AN: 151106 Hom.: 307 Cov.: 31

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000422

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00837 AC: 2103 AN: 251164 Hom.: 156 AF XY: 0.00574 AC XY: 779 AN XY: 135756

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00651

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00312 AC: 4561 AN: 1460300 Hom.: 280 Cov.: 31 AF XY: 0.00269 AC XY: 1956 AN XY: 726464

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.00660

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.00639

GnomAD4 genome AF: 0.0297 AC: 4488 AN: 151220 Hom.: 309 Cov.: 31 AF XY: 0.0283 AC XY: 2089 AN XY: 73820

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000530

Gnomad4 OTH AF: 0.0162

Alfa AF: 0.00757 Hom.: 49

Bravo AF: 0.0342

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.110 AC: 485

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0104 AC: 1259

Asia WGS AF: 0.00585 AC: 20 AN: 3432

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.90
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.026
Sift	Benign	0.12	T
Sift4G	Benign	0.081	T
Vest4		0.17
MPC		0.088
ClinPred		0.0022	T
GERP RS		-1.6
gMVP		0.21

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: rs28399454; hg19: chr19-41351267; COSMIC: COSV56536162; COSMIC: COSV56536162;