19-40848628-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.018 ( 54 hom., cov: 32)

Exomes 𝑓: 0.025 ( 699 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

drug response no assertion criteria provided O:2

Conservation

PhyloP100: 2.79

Publications

128 publications found

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 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)

CYP2A6 links:

ENSG00000268797 (HGNC:):

ENSG00000268797 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 54 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.479T>A	p.Leu160His	missense	Exon 3 of 9	NP_000753.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP2A6	ENST00000301141.10	TSL:1 MANE Select	c.479T>A	p.Leu160His	missense	Exon 3 of 9	ENSP00000301141.4	P11509
CYP2A6	ENST00000596719.5	TSL:1	n.330T>A		non_coding_transcript_exon	Exon 2 of 6
CYP2A6	ENST00000600495.1	TSL:1	n.*291T>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000472905.1	M0R2Z4

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2765

AN:

151434

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0197

AC:

4925

AN:

249708

AF XY:

0.0199

show subpopulations

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 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.:

AF XY:

0.0245

AC XY:

17761

AN XY:

726252

show subpopulations

African (AFR)

AF:

0.00407

AC:

136

AN:

33450

American (AMR)

AF:

0.0165

AC:

739

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

504

AN:

26114

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38420

South Asian (SAS)

AF:

0.0129

AC:

1115

AN:

86138

European-Finnish (FIN)

AF:

0.0242

AC:

1288

AN:

53332

Middle Eastern (MID)

AF:

0.0153

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0278

AC:

30884

AN:

1111740

Other (OTH)

AF:

0.0227

AC:

1369

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2185

4371

6556

8742

10927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1122

2244

3366

4488

5610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0183

AC:

2766

AN:

151548

Hom.:

Cov.:

AF XY:

0.0181

AC XY:

1337

AN XY:

74008

show subpopulations

African (AFR)

AF:

0.00440

AC:

182

AN:

41322

American (AMR)

AF:

0.0232

AC:

355

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3470

East Asian (EAS)

AF:

0.000204

AC:

AN:

4912

South Asian (SAS)

AF:

0.00967

AC:

AN:

4756

European-Finnish (FIN)

AF:

0.0257

AC:

271

AN:

10558

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0255

AC:

1730

AN:

67952

Other (OTH)

AF:

0.0233

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0248

Hom.:

Bravo

AF:

0.0187

TwinsUK

AF:

0.0291

AC:

108

ALSPAC

AF:

0.0272

AC:

105

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0247

AC:

212

ExAC

AF:

0.0184

AC:

2230

Asia WGS

AF:

0.00322

AC:

AN:

3430

EpiCase

AF:

0.0269

EpiControl

AF:

0.0282

ClinVar

ClinVar submissions

Significance:drug response

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

NICOTINE, POOR METABOLISM OF (1)

Warfarin response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.74

MetaRNN

Benign

0.036

MetaSVM

Uncertain

-0.25

PhyloP100

2.8

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Vest4

0.39

MPC

0.52

ClinPred

0.11

GERP RS

2.8

gMVP

0.64

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over