19-40850341-C-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.86G>A(p.Ser29Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,610,090 control chromosomes in the GnomAD database, including 2,956 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.025 ( 168 hom., cov: 31)

Exomes 𝑓: 0.040 ( 2788 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

Publications

32 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=0.002910614).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0253 (3825/151086) while in subpopulation NFE AF = 0.0408 (2768/67804). AF 95% confidence interval is 0.0396. There are 168 homozygotes in GnomAd4. There are 1798 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 168 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.86G>A	p.Ser29Asn	missense	Exon 1 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.86G>A	p.Ser29Asn	missense	Exon 1 of 9	ENSP00000301141.4	P11509
CYP2A6	ENST00000596719.5	TSL:1	n.100G>A		non_coding_transcript_exon	Exon 1 of 6
CYP2A6	ENST00000600495.1	TSL:1	n.86G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000472905.1	M0R2Z4

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3825

AN:

150972

Hom.:

168

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00842

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0207

Gnomad ASJ

AF:

0.0180

Gnomad EAS

AF:

0.000604

Gnomad SAS

AF:

0.0314

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0408

Gnomad OTH

AF:

0.0217

GnomAD2 exomes

AF:

0.0285

AC:

7153

AN:

250704

AF XY:

0.0302

show subpopulations

Gnomad AFR exome

AF:

0.00745

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0217

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0416

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0397

AC:

57862

AN:

1459004

Hom.:

2788

Cov.:

AF XY:

0.0396

AC XY:

28740

AN XY:

725842

show subpopulations

African (AFR)

AF:

0.00709

AC:

237

AN:

33444

American (AMR)

AF:

0.0154

AC:

687

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

595

AN:

26110

East Asian (EAS)

AF:

0.0000520

AC:

AN:

38428

South Asian (SAS)

AF:

0.0350

AC:

3014

AN:

86050

European-Finnish (FIN)

AF:

0.0140

AC:

749

AN:

53312

Middle Eastern (MID)

AF:

0.0220

AC:

127

AN:

5760

European-Non Finnish (NFE)

AF:

0.0454

AC:

50427

AN:

1111012

Other (OTH)

AF:

0.0336

AC:

2024

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3198

6396

9594

12792

15990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1840

3680

5520

7360

9200

<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:

0.0253

AC:

3825

AN:

151086

Hom.:

168

Cov.:

AF XY:

0.0244

AC XY:

1798

AN XY:

73790

show subpopulations

African (AFR)

AF:

0.00839

AC:

346

AN:

41226

American (AMR)

AF:

0.0206

AC:

312

AN:

15170

Ashkenazi Jewish (ASJ)

AF:

0.0180

AC:

AN:

3450

East Asian (EAS)

AF:

0.000605

AC:

AN:

4958

South Asian (SAS)

AF:

0.0312

AC:

148

AN:

4738

European-Finnish (FIN)

AF:

0.0128

AC:

134

AN:

10448

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0408

AC:

2768

AN:

67804

Other (OTH)

AF:

0.0216

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

185

369

554

738

923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0358

Hom.:

374

Bravo

AF:

0.0246

TwinsUK

AF:

0.0453

AC:

168

ALSPAC

AF:

0.0423

AC:

163

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0407

AC:

350

ExAC

AF:

0.0292

AC:

3539

Asia WGS

AF:

0.0140

AC:

AN:

3428

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.028

(source)

DANN

Benign

0.67

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

PhyloP100

-1.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.27

REVEL

Benign

0.029

Sift

Benign

0.44

Sift4G

Benign

0.47

Vest4

0.039

MPC

0.13

ClinPred

0.0023

GERP RS

-3.7

PromoterAI

0.040

Neutral

(source)

gMVP

0.083

Mutation Taster

=100/0

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

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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