rs28399433

Variant names:

• chr19-40850474-A-C
• rs28399433
• ENST00000601627.1:n.118-41517A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 157 publications found

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]

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)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.-48T>G		upstream_gene_variant		ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000268797	ENST00000601627.1	n.118-41517A>C		intron_variant	Intron 1 of 3	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

GnomAD2 exomes AF: 0.103 AC: 23305 AN: 225772 AF XY: 0.102

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 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

African (AFR) AF: 0.0812 AC: 2620 AN: 32282

American (AMR) AF: 0.136 AC: 5621 AN: 41380

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 1625 AN: 23788

East Asian (EAS) AF: 0.250 AC: 9331 AN: 37370

South Asian (SAS) AF: 0.140 AC: 11274 AN: 80386

European-Finnish (FIN) AF: 0.114 AC: 5919 AN: 51792

Middle Eastern (MID) AF: 0.0596 AC: 330 AN: 5540

European-Non Finnish (NFE) AF: 0.0644 AC: 69221 AN: 1075158

Other (OTH) AF: 0.0775 AC: 4493 AN: 57944

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

African (AFR) AF: 0.0809 AC: 3333 AN: 41182

American (AMR) AF: 0.0953 AC: 1441 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 229 AN: 3454

East Asian (EAS) AF: 0.226 AC: 1109 AN: 4916

South Asian (SAS) AF: 0.137 AC: 652 AN: 4746

European-Finnish (FIN) AF: 0.117 AC: 1214 AN: 10408

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0674 AC: 4568 AN: 67790

Other (OTH) AF: 0.0827 AC: 172 AN: 2080

Alfa AF: 0.0636 Hom.: 103

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
PhyloP100		4.7
PromoterAI		-0.0060	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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