chr19-40848628-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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. 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

Scores

Clinical Significance

drug response no assertion criteria provided O:2

Conservation

PhyloP100: 2.79

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:

ENSG00000268797 (HGNC:):

ENSG00000268797 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. 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 rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6 link	c.479T>A	p.Leu160His	missense_variant	Exon 3 of 9	ENST00000301141.10	NP_000753.3	P11509

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10 link	c.479T>A	p.Leu160His	missense_variant	Exon 3 of 9	1	NM_000762.6	ENSP00000301141.4		P11509
ENSG00000268797	ENST00000601627.1 link	n.118-43363A>T		intron_variant	Intron 1 of 3	3		ENSP00000469533.1		M0QY20

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

Gnomad4 AFR exome

AF:

0.00407

AC:

136

AN:

33450

Gnomad4 AMR exome

AF:

0.0165

AC:

739

AN:

44698

Gnomad4 ASJ exome

AF:

0.0193

AC:

504

AN:

26114

Gnomad4 EAS exome

AF:

0.0000260

AC:

AN:

38420

Gnomad4 SAS exome

AF:

0.0129

AC:

1115

AN:

86138

Gnomad4 FIN exome

AF:

0.0242

AC:

1288

AN:

53332

Gnomad4 NFE exome

AF:

0.0278

AC:

30884

AN:

1111740

Gnomad4 Remaining exome

AF:

0.0227

AC:

1369

AN:

60266

Heterozygous variant carriers

2185

4371

6556

8742

10927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Gnomad4 AFR

AF:

0.00440

AC:

0.00440443

AN:

0.00440443

Gnomad4 AMR

AF:

0.0232

AC:

0.0232452

AN:

0.0232452

Gnomad4 ASJ

AF:

0.0216

AC:

0.0216138

AN:

0.0216138

Gnomad4 EAS

AF:

0.000204

AC:

0.000203583

AN:

0.000203583

Gnomad4 SAS

AF:

0.00967

AC:

0.00967199

AN:

0.00967199

Gnomad4 FIN

AF:

0.0257

AC:

0.0256677

AN:

0.0256677

Gnomad4 NFE

AF:

0.0255

AC:

0.0254591

AN:

0.0254591

Gnomad4 OTH

AF:

0.0233

AC:

0.0233333

AN:

0.0233333

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Significance: drug response

Submissions summary: Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Warfarin response

Other:1

Sep 01, 2000

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nicotine, poor metabolism of

Other:1

Sep 01, 2000

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

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

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)

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