dbSNP rs5031016: CYP2A6:p.Ile471Thr (chr19-40843869-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000762.6(CYP2A6):c.1412T>C(p.Ile471Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00603 in 151,060 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0060 ( 25 hom., cov: 30)

Exomes 𝑓: 0.0055 ( 85 hom. )

Failed GnomAD Quality Control

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.84

Publications

52 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=0.0038813949).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A6	NM_000762.6	MANE Select	c.1412T>C	p.Ile471Thr	missense	Exon 9 of 9	NP_000753.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP2A6	ENST00000301141.10	TSL:1 MANE Select	c.1412T>C	p.Ile471Thr	missense	Exon 9 of 9	ENSP00000301141.4
ENSG00000268797	ENST00000601627.1	TSL:3	n.117+42454A>G		intron	N/A	ENSP00000469533.1
CYP2A6	ENST00000599960.1	TSL:2	n.331T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00608

AC:

918

AN:

150944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000561

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00185

Gnomad ASJ

AF:

0.0142

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.00760

Gnomad FIN

AF:

0.000285

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.00820

GnomAD2 exomes

AF:

0.00813

AC:

2023

AN:

248754

AF XY:

0.00752

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.00687

Gnomad EAS exome

AF:

0.0990

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.00543

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00549

AC:

8004

AN:

1457534

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

3952

AN XY:

724966

show subpopulations

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

African (AFR)

AF:

0.000538

AC:

AN:

33450

American (AMR)

AF:

0.00168

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

302

AN:

25890

East Asian (EAS)

AF:

0.136

AC:

5140

AN:

37746

South Asian (SAS)

AF:

0.00284

AC:

244

AN:

85942

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00679

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00151

AC:

1678

AN:

1110690

Other (OTH)

AF:

0.00813

AC:

488

AN:

60048

⚠️ 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: 0.358

Heterozygous variant carriers

437

874

1312

1749

2186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00603

AC:

911

AN:

151060

Hom.:

Cov.:

AF XY:

0.00628

AC XY:

463

AN XY:

73760

show subpopulations

African (AFR)

AF:

0.000559

AC:

AN:

41156

American (AMR)

AF:

0.00185

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.0142

AC:

AN:

3456

East Asian (EAS)

AF:

0.127

AC:

616

AN:

4844

South Asian (SAS)

AF:

0.00740

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.000285

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00197

AC:

134

AN:

67890

Other (OTH)

AF:

0.00812

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.402

Heterozygous variant carriers

101

135

169

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:

0.00411

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0113

AC:

1366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.1

PhyloP100

4.8

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.25

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Vest4

0.27

MPC

4.0

ClinPred

0.061

GERP RS

2.9

gMVP

0.39

Mutation Taster

=100/0

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