Genetic Variant NM_000762.6:c.1420T>C (chr19-40843861-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000762.6(CYP2A6):c.1420T>C(p.Ser474Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Consequence

CYP2A6
NM_000762.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.724

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21056953).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000762.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A6	NM_000762.6	MANE Select	c.1420T>C	p.Ser474Pro	missense	Exon 9 of 9	NP_000753.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP2A6	ENST00000301141.10	TSL:1 MANE Select	c.1420T>C	p.Ser474Pro	missense	Exon 9 of 9	ENSP00000301141.4	P11509
ENSG00000268797	ENST00000601627.1	TSL:3	n.117+42446A>G		intron	N/A	ENSP00000469533.1	M0QY20
CYP2A6	ENST00000874215.1		c.1510T>C	p.Ser504Pro	missense	Exon 9 of 9	ENSP00000544274.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.36

M_CAP

Benign

0.036

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.98

PhyloP100

-0.72

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.067

Sift

Uncertain

0.016

Sift4G

Uncertain

0.0050

Vest4

0.11

MutPred

0.45

Gain of catalytic residue at S474 (P = 0.0015)

MVP

0.65

MPC

2.5

ClinPred

0.45

GERP RS

0.72

gMVP

0.66

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over