rs8192730

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.1257G>C(p.Glu419Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,610,716 control chromosomes in the GnomAD database, including 64 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 0.0070 ( 31 hom., cov: 31)

Exomes 𝑓: 0.00057 ( 33 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.92

Publications

13 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=0.0034837425).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00702 (1063/151482) while in subpopulation AFR AF = 0.0237 (977/41228). AF 95% confidence interval is 0.0225. There are 31 homozygotes in GnomAd4. There are 518 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 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.1257G>C	p.Glu419Asp	missense	Exon 8 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.1257G>C	p.Glu419Asp	missense	Exon 8 of 9	ENSP00000301141.4	P11509
ENSG00000268797	ENST00000601627.1	TSL:3	n.117+43262C>G		intron	N/A	ENSP00000469533.1	M0QY20
CYP2A6	ENST00000874215.1		c.1347G>C	p.Glu449Asp	missense	Exon 8 of 9	ENSP00000544274.1

Frequencies

GnomAD3 genomes

AF:

0.00702

AC:

1063

AN:

151368

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00361

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00141

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00385

GnomAD2 exomes

AF:

0.000822

AC:

206

AN:

250620

AF XY:

0.000583

show subpopulations

Gnomad AFR exome

AF:

0.00989

Gnomad AMR exome

AF:

0.000754

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000331

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000574

AC:

838

AN:

1459234

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

364

AN XY:

726026

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0141

AC:

465

AN:

32896

American (AMR)

AF:

0.00152

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000911

AC:

AN:

38434

South Asian (SAS)

AF:

0.000290

AC:

AN:

86088

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000155

AC:

172

AN:

1111676

Other (OTH)

AF:

0.00105

AC:

AN:

60234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.391

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00702

AC:

1063

AN:

151482

Hom.:

Cov.:

AF XY:

0.00700

AC XY:

518

AN XY:

74006

show subpopulations

African (AFR)

AF:

0.0237

AC:

977

AN:

41228

American (AMR)

AF:

0.00354

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00141

AC:

AN:

4964

South Asian (SAS)

AF:

0.000210

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

67964

Other (OTH)

AF:

0.00381

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00182

Hom.:

Bravo

AF:

0.00739

ExAC

AF:

0.00210

AC:

255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.50

CADD

Benign

3.0

(source)

DANN

Benign

0.93

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

PhyloP100

-1.9

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

REVEL

Benign

0.092

Sift

Benign

0.23

Sift4G

Benign

0.27

Vest4

0.065

MutPred

0.20

Loss of methylation at K420 (P = 0.0922)

MVP

0.24

MPC

0.076

ClinPred

0.00079

GERP RS

-1.6

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(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