chr19-40844725-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_000762.6(CYP2A6):c.1209T>C(p.Ser403Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,611,118 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0048 ( 9 hom., cov: 31)

Exomes 𝑓: 0.0064 ( 105 hom. )

Consequence

CYP2A6
NM_000762.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 19-40844725-A-G is Benign according to our data. Variant chr19-40844725-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2649913.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.84 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 9 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6 link	c.1209T>C	p.Ser403Ser	synonymous_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>C	p.Ser403Ser	synonymous_variant	Exon 8 of 9	1	NM_000762.6	ENSP00000301141.4	P11509
ENSG00000268797	ENST00000601627.1 link	n.117+43310A>G		intron_variant	Intron 1 of 3	3		ENSP00000469533.1	M0QY20
CYP2A6	ENST00000599960.1 link	n.128T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
CYP2A6	ENST00000596719.5 link	n.*197T>C		downstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00482

AC:

729

AN:

151336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00881

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00121

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.00408

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00631

Gnomad OTH

AF:

0.00481

GnomAD2 exomes

AF:

0.00511

AC:

1284

AN:

251054

AF XY:

0.00510

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00599

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00143

Gnomad FIN exome

AF:

0.00615

Gnomad NFE exome

AF:

0.00678

Gnomad OTH exome

AF:

0.00816

GnomAD4 exome

AF:

0.00642

AC:

9373

AN:

1459666

Hom.:

105

Cov.:

AF XY:

0.00633

AC XY:

4600

AN XY:

726168

show subpopulations

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

African (AFR)

AF:

0.00123

AC:

AN:

33450

American (AMR)

AF:

0.00615

AC:

275

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00429

AC:

112

AN:

26134

East Asian (EAS)

AF:

0.000416

AC:

AN:

38424

South Asian (SAS)

AF:

0.00105

AC:

AN:

86110

European-Finnish (FIN)

AF:

0.00652

AC:

348

AN:

53362

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00730

AC:

8117

AN:

1111442

Other (OTH)

AF:

0.00607

AC:

366

AN:

60260

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.383

Heterozygous variant carriers

401

802

1203

1604

2005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00483

AC:

732

AN:

151452

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

335

AN XY:

73982

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

41244

American (AMR)

AF:

0.0104

AC:

158

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3468

East Asian (EAS)

AF:

0.00121

AC:

AN:

4960

South Asian (SAS)

AF:

0.00105

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.00408

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00633

AC:

430

AN:

67942

Other (OTH)

AF:

0.00477

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00310

Hom.:

Bravo

AF:

0.00556

EpiCase

AF:

0.00573

EpiControl

AF:

0.00605

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP2A6: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.0

(source)

DANN

Benign

0.50

PhyloP100

-2.8

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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chr19-40844725-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over