rs5031016

Variant names:

• chr19-40843869-A-G
• rs5031016
• NM_000762.6:c.1412T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000762.6(CYP2A6):​c.1412T>C​(p.Ile471Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00603 in 151,060 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0060 (25 hom., cov: 30)
  • Exomes 𝑓: 0.0055 (85 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.84

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]

ENSG00000268797 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038813949).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.1412T>C	p.Ile471Thr	missense_variant	Exon 9 of 9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.1412T>C	p.Ile471Thr	missense_variant	Exon 9 of 9	1	NM_000762.6	ENSP00000301141.4
ENSG00000268797	ENST00000601627.1	n.117+42454A>G		intron_variant	Intron 1 of 3	3		ENSP00000469533.1
CYP2A6	ENST00000599960.1	n.331T>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 918 AN: 150944 Hom.: 25 Cov.: 30

Gnomad AFR AF: 0.000561

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00185

Gnomad ASJ AF: 0.0142

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.00760

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00820

GnomAD3 exomes AF: 0.00813 AC: 2023 AN: 248754 Hom.: 13 AF XY: 0.00752 AC XY: 1011 AN XY: 134460

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00687

Gnomad EAS exome AF: 0.0990

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00543

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00549 AC: 8004 AN: 1457534 Hom.: 85 Cov.: 33 AF XY: 0.00545 AC XY: 3952 AN XY: 724966

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.136

Gnomad4 SAS exome AF: 0.00284

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.00813

GnomAD4 genome AF: 0.00603 AC: 911 AN: 151060 Hom.: 25 Cov.: 30 AF XY: 0.00628 AC XY: 463 AN XY: 73760

Gnomad4 AFR AF: 0.000559

Gnomad4 AMR AF: 0.00185

Gnomad4 ASJ AF: 0.0142

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.00740

Gnomad4 FIN AF: 0.000285

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.00812

Alfa AF: 0.00414 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0113 AC: 1366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.27
MPC		4.0
ClinPred		0.061	T
GERP RS		2.9
gMVP		0.39

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: rs5031016; hg19: chr19-41349774; COSMIC: COSV56534871; COSMIC: COSV56534871;