19-40843861-A-G

Position:

• chr19-40843861-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 12/19 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.724

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21056953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.1420T>C	p.Ser474Pro	missense_variant	9/9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.1420T>C	p.Ser474Pro	missense_variant	9/9	1	NM_000762.6	ENSP00000301141	P1
CYP2A6	ENST00000599960.1	n.339T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2022

The c.1420T>C (p.S474P) alteration is located in exon 9 (coding exon 9) of the CYP2A6 gene. This alteration results from a T to C substitution at nucleotide position 1420, causing the serine (S) at amino acid position 474 to be replaced by a proline (P). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.067
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0050	D
Vest4		0.11
MutPred		0.45		Gain of catalytic residue at S474 (P = 0.0015);
MVP		0.65
MPC		2.5
ClinPred		0.45	T
GERP RS		0.72
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-41349766;