chr19-40848628-A-T

Position:

• chr19-40848628-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000762.6(CYP2A6):​c.479T>A​(p.Leu160His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,611,470 control chromosomes in the GnomAD database, including 753 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L160I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (54 hom., cov: 32)
  • Exomes 𝑓: 0.025 (699 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: drug response no assertion criteria provided O:2
• Conservation: PhyloP100: 2.79

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036087453).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0183 (2766/151548) while in subpopulation NFE AF= 0.0255 (1730/67952). AF 95% confidence interval is 0.0245. There are 54 homozygotes in gnomad4. There are 1337 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2766 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.479T>A	p.Leu160His	missense_variant	3/9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.479T>A	p.Leu160His	missense_variant	3/9	1	NM_000762.6	ENSP00000301141	P1
CYP2A6	ENST00000596719.5	n.330T>A		non_coding_transcript_exon_variant	2/6	1
CYP2A6	ENST00000600495.1	c.*291T>A		3_prime_UTR_variant, NMD_transcript_variant	3/6	1		ENSP00000472905

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2765 AN: 151434 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00966

Gnomad FIN AF: 0.0257

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0235

GnomAD3 exomes AF: 0.0197 AC: 4925 AN: 249708 Hom.: 103 AF XY: 0.0199 AC XY: 2698 AN XY: 135270

Gnomad AFR exome AF: 0.00433

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0120

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0267

Gnomad OTH exome AF: 0.0234

GnomAD4 exome AF: 0.0247 AC: 36124 AN: 1459922 Hom.: 699 Cov.: 61 AF XY: 0.0245 AC XY: 17761 AN XY: 726252

Gnomad4 AFR exome AF: 0.00407

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0242

Gnomad4 NFE exome AF: 0.0278

Gnomad4 OTH exome AF: 0.0227

GnomAD4 genome AF: 0.0183 AC: 2766 AN: 151548 Hom.: 54 Cov.: 32 AF XY: 0.0181 AC XY: 1337 AN XY: 74008

Gnomad4 AFR AF: 0.00440

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.000204

Gnomad4 SAS AF: 0.00967

Gnomad4 FIN AF: 0.0257

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0233

Alfa AF: 0.0248 Hom.: 22

Bravo AF: 0.0187

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0272 AC: 105

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0247 AC: 212

ExAC AF: 0.0184 AC: 2230

Asia WGS AF: 0.00322 AC: 11 AN: 3430

EpiCase AF: 0.0269

EpiControl AF: 0.0282

ClinVar

Significance: drug response

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Warfarin response Other:1

drug response, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

Nicotine, poor metabolism of Other:1

drug response, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.95
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.036	T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	2.1e-10	A
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Vest4		0.39
MPC		0.52
ClinPred		0.11	T
GERP RS		2.8
gMVP		0.64

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: rs1801272; hg19: chr19-41354533;