rs1809810

Positions:

• chr19-40844759-T-A
• chr19-40844759-T-C
• chr19-40844759-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000762.6(CYP2A6):​c.1175A>T​(p.Tyr392Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,604,908 control chromosomes in the GnomAD database, including 454 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.012 (30 hom., cov: 31)
  • Exomes 𝑓: 0.013 (424 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02219364).
• BS2: High AC in GnomAd4 at 1815 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2A6	NM_000762.6	c.1175A>T	p.Tyr392Phe	missense_variant	8/9	ENST00000301141.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2A6	ENST00000301141.10	c.1175A>T	p.Tyr392Phe	missense_variant	8/9	1	NM_000762.6	P1
CYP2A6	ENST00000599960.1	n.94A>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1815 AN: 151144 Hom.: 30 Cov.: 31

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0128 AC: 18613 AN: 1453650 Hom.: 424 Cov.: 32 AF XY: 0.0129 AC XY: 9303 AN XY: 723290

Gnomad4 AFR exome AF: 0.00554

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00990

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0120 AC: 1815 AN: 151258 Hom.: 30 Cov.: 31 AF XY: 0.0119 AC XY: 877 AN XY: 73870

Gnomad4 AFR AF: 0.00522

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.0115

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.0137 Hom.: 8

Bravo AF: 0.0125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	12
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.022	T
Sift4G	Benign	1.0	T
Vest4		0.21
gMVP		0.25

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1809810; hg19: chr19-41350664;