chr19-40846886-G-T

Variant names:

• chr19-40846886-G-T
• rs780129128
• NM_000762.6:c.820C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000762.6(CYP2A6):​c.820C>A​(p.Arg274Ser) 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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0270
• Publications: 1 publications found

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)

ENSG00000268797 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3696476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.820C>A	p.Arg274Ser	missense_variant	Exon 5 of 9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.820C>A	p.Arg274Ser	missense_variant	Exon 5 of 9	1	NM_000762.6	ENSP00000301141.4
ENSG00000268797	ENST00000601627.1	n.118-45105G>T		intron_variant	Intron 1 of 3	3		ENSP00000469533.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.032	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.84	T
PhyloP100		0.027
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.41
MutPred		0.50		Gain of disorder (P = 0.0802);
MVP		0.76
MPC		0.44
ClinPred		0.98	D
GERP RS		1.1
gMVP		0.45
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs780129128; hg19: chr19-41352791;