chr19-40846030-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_000762.6(CYP2A6):c.899T>C(p.Ile300Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,611,506 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00040 ( 11 hom. )

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.471

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 -4 ACMG points.

PM1

In a mutagenesis_site Increases phenacetin O-deethylation activity 3 fold. Increases phenacetin O-deethylation activity 8 fold; when associated with A-301. Increases phenacetin O-deethylation activity 10 fold; when associated with S-208 and A-301. Increases phenacetin O-deethylation activity 12 fold; when associated with A-301 and G-369. Increases phenacetin O-deethylation activity 38 fold; when associated with S-208; A-301 and G-369. (size 0) in uniprot entity CP2A6_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.07926196).

BS2

High Homozygotes in GnomAdExome4 at 11 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6 link	c.899T>C	p.Ile300Thr	missense_variant	Exon 6 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.899T>C	p.Ile300Thr	missense_variant	Exon 6 of 9	1	NM_000762.6	ENSP00000301141.4		P11509
ENSG00000268797	ENST00000601627.1 link	n.117+44615A>G		intron_variant	Intron 1 of 3	3		ENSP00000469533.1		M0QY20

Frequencies

GnomAD3 genomes

AF:

0.000291

AC:

AN:

151136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000975

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000460

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000843

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000398

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000299

AC:

AN:

251126

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000221

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000399

AC:

582

AN:

1460254

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

301

AN XY:

726440

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33452

American (AMR)

AF:

0.000157

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000260

AC:

AN:

38440

South Asian (SAS)

AF:

0.000348

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000448

AC:

498

AN:

1111944

Other (OTH)

AF:

0.000498

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000284

AC:

AN:

151252

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

AN XY:

73858

show subpopulations

African (AFR)

AF:

0.0000972

AC:

AN:

41146

American (AMR)

AF:

0.000459

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

4926

South Asian (SAS)

AF:

0.000844

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000398

AC:

AN:

67898

Other (OTH)

AF:

0.000477

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000300

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000585

AC:

AN:

3432

EpiCase

AF:

0.000491

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.899T>C (p.I300T) alteration is located in exon 6 (coding exon 6) of the CYP2A6 gene. This alteration results from a T to C substitution at nucleotide position 899, causing the isoleucine (I) at amino acid position 300 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.88

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.76

M_CAP

Benign

0.030

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.88

PhyloP100

0.47

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

REVEL

Benign

0.13

Sift

Benign

0.10

Sift4G

Benign

0.13

Vest4

0.23

MVP

0.65

MPC

0.25

ClinPred

0.0068

GERP RS

2.4

gMVP

0.25

Mutation Taster

=87/13

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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chr19-40846030-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