Genetic Variant CYP2A6:p.Thr294Ser (chr19-40846048-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000762.6(CYP2A6):c.881C>G(p.Thr294Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,611,586 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.000099 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.205

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.074441165).

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.881C>G	p.Thr294Ser	missense	Exon 6 of 9	NP_000753.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP2A6	ENST00000301141.10	TSL:1 MANE Select	c.881C>G	p.Thr294Ser	missense	Exon 6 of 9	ENSP00000301141.4
CYP2A6	ENST00000596719.5	TSL:1	n.732C>G		non_coding_transcript_exon	Exon 5 of 6
CYP2A6	ENST00000600495.1	TSL:1	n.*693C>G		non_coding_transcript_exon	Exon 6 of 6	ENSP00000472905.1

Frequencies

GnomAD3 genomes

AF:

0.0000992

AC:

AN:

151224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251110

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460248

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

726442

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33456

American (AMR)

AF:

0.0000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

38440

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111932

Other (OTH)

AF:

0.0000498

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.416

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000991

AC:

AN:

151338

Hom.:

Cov.:

AF XY:

0.0000947

AC XY:

AN XY:

73914

show subpopulations

African (AFR)

AF:

0.000364

AC:

AN:

41194

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

4930

South Asian (SAS)

AF:

0.00

AC:

AN:

4736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67910

Other (OTH)

AF:

0.00

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000585

AC:

AN:

3432

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.36

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.38

M_CAP

Benign

0.032

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.92

PhyloP100

-0.20

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.4

REVEL

Benign

0.12

Sift

Benign

0.19

Sift4G

Benign

0.19

Vest4

0.078

MutPred

0.27

Loss of ubiquitination at K289 (P = 0.1651)

MVP

0.49

MPC

0.13

ClinPred

0.11

GERP RS

1.3

gMVP

0.20

Mutation Taster

=95/5

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