19-40844759-T-A

Variant names:

• chr19-40844759-T-A
• rs1809810
• NM_000762.6:c.1175A>T

Variant summary

Our verdict is Benign. The variant received -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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Y392C) has been classified as Uncertain significance.

• 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
• Publications: 35 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02219364).
• BS2: High Homozygotes in GnomAd4 at 30 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000762.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A6	NM_000762.6	MANE Select	c.1175A>T	p.Tyr392Phe	missense	Exon 8 of 9	NP_000753.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A6	ENST00000301141.10	TSL:1 MANE Select	c.1175A>T	p.Tyr392Phe	missense	Exon 8 of 9	ENSP00000301141.4	P11509
	ENSG00000268797	ENST00000601627.1	TSL:3	n.117+43344T>A		intron	N/A	ENSP00000469533.1	M0QY20
	CYP2A6	ENST00000874215.1		c.1265A>T	p.Tyr422Phe	missense	Exon 8 of 9	ENSP00000544274.1

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

African (AFR) AF: 0.00554 AC: 185 AN: 33420

American (AMR) AF: 0.0102 AC: 456 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 263 AN: 26108

East Asian (EAS) AF: 0.00990 AC: 380 AN: 38378

South Asian (SAS) AF: 0.0116 AC: 1000 AN: 86010

European-Finnish (FIN) AF: 0.0138 AC: 735 AN: 53322

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5762

European-Non Finnish (NFE) AF: 0.0132 AC: 14652 AN: 1105910

Other (OTH) AF: 0.0145 AC: 874 AN: 60094

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

African (AFR) AF: 0.00522 AC: 215 AN: 41188

American (AMR) AF: 0.0164 AC: 249 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3466

East Asian (EAS) AF: 0.0115 AC: 57 AN: 4936

South Asian (SAS) AF: 0.0133 AC: 63 AN: 4744

European-Finnish (FIN) AF: 0.0125 AC: 131 AN: 10516

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1017 AN: 67882

Other (OTH) AF: 0.0119 AC: 25 AN: 2100

Alfa AF: 0.0137 Hom.: 8

Bravo AF: 0.0125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
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

Other links and lift over

dbSNP: rs1809810; hg19: chr19-41350664;