Genetic Variant NM_000762.6:c.1209T>G (chr19-40844725-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000762.6(CYP2A6):c.1209T>G(p.Ser403Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,611,494 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S403S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 5 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.84

Publications

2 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03546241).

BS2

High Homozygotes in GnomAdExome4 at 5 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6 link	c.1209T>G	p.Ser403Arg	missense_variant	Exon 8 of 9	ENST00000301141.10	NP_000753.3	P11509

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2A6	ENST00000301141.10 link	c.1209T>G	p.Ser403Arg	missense_variant	Exon 8 of 9	1	NM_000762.6	ENSP00000301141.4	P11509
ENSG00000268797	ENST00000601627.1 link	n.117+43310A>C		intron_variant	Intron 1 of 3	3		ENSP00000469533.1	M0QY20
CYP2A6	ENST00000599960.1 link	n.128T>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
CYP2A6	ENST00000596719.5 link	n.*197T>G		downstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000595

AC:

AN:

151340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000677

AC:

AN:

251054

AF XY:

0.0000811

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000386

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

178

AN:

1460154

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

726392

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000573

AC:

AN:

38426

South Asian (SAS)

AF:

0.00

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000134

AC:

149

AN:

1111862

Other (OTH)

AF:

0.0000829

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000595

AC:

AN:

151340

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41122

American (AMR)

AF:

0.00

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000201

AC:

AN:

4970

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.47

(source)

DANN

Benign

0.90

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.20

M_CAP

Benign

0.020

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.1

PhyloP100

-2.8

PrimateAI

Benign

0.31

PROVEAN

Benign

0.71

REVEL

Benign

0.048

Sift

Benign

0.14

Sift4G

Benign

0.17

Vest4

0.14

MutPred

0.36

Loss of phosphorylation at S403 (P = 0.029);

MVP

0.31

MPC

0.094

ClinPred

0.020

GERP RS

-1.3

gMVP

0.11

Mutation Taster

=94/6

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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NM_000762.6:c.1209T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over