19-40848635-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000762.6(CYP2A6):c.472G>T(p.Asp158Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D158E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.814

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29105818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2A6	NM_000762.6 linkuse as main transcript	c.472G>T	p.Asp158Tyr	missense_variant	3/9	ENST00000301141.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CYP2A6	ENST00000301141.10 linkuse as main transcript	c.472G>T	p.Asp158Tyr	missense_variant	3/9	1	NM_000762.6	P1
CYP2A6	ENST00000596719.5 linkuse as main transcript	n.323G>T		non_coding_transcript_exon_variant	2/6	1
CYP2A6	ENST00000600495.1 linkuse as main transcript	c.*284G>T		3_prime_UTR_variant, NMD_transcript_variant	3/6	1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250096

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135436

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460076

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726350

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151628

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73974

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.472G>T (p.D158Y) alteration is located in exon 3 (coding exon 3) of the CYP2A6 gene. This alteration results from a G to T substitution at nucleotide position 472, causing the aspartic acid (D) at amino acid position 158 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.32

Cadd

Benign

8.5

Dann

Benign

0.92

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.67

M_CAP

Benign

0.021

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.61

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.30

MutPred

0.60

Gain of catalytic residue at I157 (P = 0.1254);

MVP

0.57

MPC

0.18

ClinPred

0.87

GERP RS

-4.9

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over