Genetic Variant CYP2A6:p.Arg203Ser (chr19-40848266-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000762.6(CYP2A6):c.607C>A(p.Arg203Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,611,482 control chromosomes in the GnomAD database, including 1 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.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.20

Publications

20 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036315173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6 link	c.607C>A	p.Arg203Ser	missense_variant	Exon 4 of 9	ENST00000301141.10	NP_000753.3	P11509

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10 link	c.607C>A	p.Arg203Ser	missense_variant	Exon 4 of 9	1	NM_000762.6	ENSP00000301141.4		P11509
ENSG00000268797	ENST00000601627.1 link	n.118-43725G>T		intron_variant	Intron 1 of 3	3		ENSP00000469533.1		M0QY20

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000204

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000119

AC:

AN:

251130

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000197

AC:

288

AN:

1460278

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

137

AN XY:

726446

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

38430

South Asian (SAS)

AF:

0.000139

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000237

AC:

264

AN:

1111960

Other (OTH)

AF:

0.000133

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000119

AC:

AN:

151204

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

73856

show subpopulations

African (AFR)

AF:

0.0000487

AC:

AN:

41082

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000204

AC:

AN:

4896

South Asian (SAS)

AF:

0.00

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

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:

0.00266

Hom.:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.2

(source)

DANN

Benign

0.22

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.043

M_CAP

Benign

0.041

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

PhyloP100

-1.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.26

REVEL

Benign

0.028

Sift

Benign

0.59

Sift4G

Benign

0.62

Vest4

0.13

MVP

0.37

MPC

0.10

ClinPred

0.014

GERP RS

-1.7

gMVP

0.43

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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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