19-40846953-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000762.6(CYP2A6):c.753G>T(p.Lys251Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,612,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.418

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26102498).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2A6	NM_000762.6	c.753G>T	p.Lys251Asn	missense_variant	5/9	ENST00000301141.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2A6	ENST00000301141.10	c.753G>T	p.Lys251Asn	missense_variant	5/9	1	NM_000762.6	P1
CYP2A6	ENST00000596719.5	n.604G>T		non_coding_transcript_exon_variant	4/6	1
CYP2A6	ENST00000600495.1	c.*565G>T		3_prime_UTR_variant, NMD_transcript_variant	5/6	1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151748 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 251136 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000507 AC: 74 AN: 1460256 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 726434

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151864 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74222

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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

Jul 05, 2023

The c.753G>T (p.K251N) alteration is located in exon 5 (coding exon 5) of the CYP2A6 gene. This alteration results from a G to T substitution at nucleotide position 753, causing the lysine (K) at amino acid position 251 to be replaced by an asparagine (N). 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	Pathogenic	0.77
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Uncertain	1.0
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.29
Sift	Benign	0.065	T
Sift4G	Benign	0.094	T
Vest4		0.44
MutPred		0.60		Loss of ubiquitination at K251 (P = 0.0283);
MVP		0.69
MPC		0.50
ClinPred		0.55	D
GERP RS		-0.032
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs374784083; hg19: chr19-41352858; COSMIC: COSV56535086; COSMIC: COSV56535086;