rs28399433

Positions:

• chr19-40850474-A-C
• chr19-40850474-A-G
• chr19-40850474-A-T

Variant summary

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

The ENST00000601627.1(ENSG00000268797):​n.118-41517A>C variant causes a intron change. The variant allele was found at a frequency of 0.0791 in 1,556,546 control chromosomes in the GnomAD database, including 9,517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.085 (974 hom., cov: 30)
  • Exomes 𝑓: 0.079 (8543 hom.)
• Consequence: ENSG00000268797 ENST00000601627.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68

Genes affected

ENSG00000268797 (HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.40850474A>C		intergenic_region
CYP2A6	NM_000762.6	c.-48T>G		upstream_gene_variant		ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000268797	ENST00000601627.1	n.118-41517A>C		intron_variant		3		ENSP00000469533.1
CYP2A6	ENST00000301141.10	c.-48T>G		upstream_gene_variant		1	NM_000762.6	ENSP00000301141.4
CYP2A6	ENST00000596719.5	n.-34T>G		upstream_gene_variant		1
CYP2A6	ENST00000600495.1	n.-48T>G		upstream_gene_variant		1		ENSP00000472905.1

Frequencies

GnomAD3 genomes AF: 0.0845 AC: 12744 AN: 150792 Hom.: 968 Cov.: 30

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0948

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0674

Gnomad OTH AF: 0.0834

GnomAD3 exomes AF: 0.103 AC: 23305 AN: 225772 Hom.: 2063 AF XY: 0.102 AC XY: 12407 AN XY: 121208

Gnomad AFR exome AF: 0.0826

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.0710

Gnomad EAS exome AF: 0.225

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0661

Gnomad OTH exome AF: 0.0867

GnomAD4 exome AF: 0.0786 AC: 110434 AN: 1405640 Hom.: 8543 Cov.: 29 AF XY: 0.0803 AC XY: 55917 AN XY: 696236

Gnomad4 AFR exome AF: 0.0812

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.0683

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.0644

Gnomad4 OTH exome AF: 0.0775

GnomAD4 genome AF: 0.0845 AC: 12753 AN: 150906 Hom.: 974 Cov.: 30 AF XY: 0.0877 AC XY: 6457 AN XY: 73656

Gnomad4 AFR AF: 0.0809

Gnomad4 AMR AF: 0.0953

Gnomad4 ASJ AF: 0.0663

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0674

Gnomad4 OTH AF: 0.0827

Alfa AF: 0.0528 Hom.: 102

Bravo AF: 0.0836

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.56

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: rs28399433; hg19: chr19-41356379; COSMIC: COSV56534388;