Genetic Variant CYP2A6:p.Ser29Asn (chr19-40850341-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000762.6(CYP2A6):c.86G>A(p.Ser29Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,610,090 control chromosomes in the GnomAD database, including 2,956 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.025 ( 168 hom., cov: 31)

Exomes 𝑓: 0.040 ( 2788 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

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 links:

ENSG00000268797 (HGNC:):

ENSG00000268797 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002910614).

BP6

Variant 19-40850341-C-T is Benign according to our data. Variant chr19-40850341-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0253 (3825/151086) while in subpopulation NFE AF= 0.0408 (2768/67804). AF 95% confidence interval is 0.0396. There are 168 homozygotes in gnomad4. There are 1798 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3825 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6 link	c.86G>A	p.Ser29Asn	missense_variant	Exon 1 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.86G>A	p.Ser29Asn	missense_variant	Exon 1 of 9	1	NM_000762.6	ENSP00000301141.4	P11509
CYP2A6	ENST00000596719.5 link	n.100G>A		non_coding_transcript_exon_variant	Exon 1 of 6	1
CYP2A6	ENST00000600495.1 link	n.86G>A		non_coding_transcript_exon_variant	Exon 1 of 6	1		ENSP00000472905.1	M0R2Z4
ENSG00000268797	ENST00000601627.1 link	n.118-41650C>T		intron_variant	Intron 1 of 3	3		ENSP00000469533.1	M0QY20

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3825

AN:

150972

Hom.:

168

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00842

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0207

Gnomad ASJ

AF:

0.0180

Gnomad EAS

AF:

0.000604

Gnomad SAS

AF:

0.0314

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0408

Gnomad OTH

AF:

0.0217

GnomAD3 exomes

AF:

0.0285

AC:

7153

AN:

250704

Hom.:

347

AF XY:

0.0302

AC XY:

4092

AN XY:

135510

show subpopulations

Gnomad AFR exome

AF:

0.00745

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0217

Gnomad EAS exome

AF:

0.0000551

Gnomad SAS exome

AF:

0.0360

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0416

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0397

AC:

57862

AN:

1459004

Hom.:

2788

Cov.:

AF XY:

0.0396

AC XY:

28740

AN XY:

725842

show subpopulations

Gnomad4 AFR exome

AF:

0.00709

Gnomad4 AMR exome

AF:

0.0154

Gnomad4 ASJ exome

AF:

0.0228

Gnomad4 EAS exome

AF:

0.0000520

Gnomad4 SAS exome

AF:

0.0350

Gnomad4 FIN exome

AF:

0.0140

Gnomad4 NFE exome

AF:

0.0454

Gnomad4 OTH exome

AF:

0.0336

GnomAD4 genome

AF:

0.0253

AC:

3825

AN:

151086

Hom.:

168

Cov.:

AF XY:

0.0244

AC XY:

1798

AN XY:

73790

show subpopulations

Gnomad4 AFR

AF:

0.00839

Gnomad4 AMR

AF:

0.0206

Gnomad4 ASJ

AF:

0.0180

Gnomad4 EAS

AF:

0.000605

Gnomad4 SAS

AF:

0.0312

Gnomad4 FIN

AF:

0.0128

Gnomad4 NFE

AF:

0.0408

Gnomad4 OTH

AF:

0.0216

Alfa

AF:

0.0354

Hom.:

Bravo

AF:

0.0246

TwinsUK

AF:

0.0453

AC:

168

ALSPAC

AF:

0.0423

AC:

163

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0407

AC:

350

ExAC

AF:

0.0292

AC:

3539

Asia WGS

AF:

0.0140

AC:

AN:

3428

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.028

DANN

Benign

0.67

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.27

REVEL

Benign

0.029

Sift

Benign

0.44

Sift4G

Benign

0.47

Vest4

0.039

MPC

0.13

ClinPred

0.0023

GERP RS

-3.7

gMVP

0.083

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over