rs8192726

chr19-40848591-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000762.6(CYP2A6):c.493+23G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0706 in 1,606,586 control chromosomes in the GnomAD database, including 6,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.074 (644 hom., cov: 31)
  • Exomes 𝑓: 0.070 (5472 hom.)
• Consequence: CYP2A6 NM_000762.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-40848591-C-A is Benign according to our data. Variant chr19-40848591-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2A6	NM_000762.6	c.493+23G>T		intron_variant		ENST00000301141.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2A6	ENST00000301141.10	c.493+23G>T		intron_variant		1	NM_000762.6	P1
CYP2A6	ENST00000600495.1	c.*305+23G>T		intron_variant, NMD_transcript_variant		1
CYP2A6	ENST00000596719.5	n.344+23G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0742 AC: 11227 AN: 151376 Hom.: 642 Cov.: 31

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0693

GnomAD3 exomes AF: 0.0794 AC: 19611 AN: 247084 Hom.: 1239 AF XY: 0.0817 AC XY: 10958 AN XY: 134088

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.0470

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.0989

Gnomad NFE exome AF: 0.0633

Gnomad OTH exome AF: 0.0698

GnomAD4 exome AF: 0.0702 AC: 102180 AN: 1455096 Hom.: 5472 Cov.: 52 AF XY: 0.0723 AC XY: 52268 AN XY: 722838

Gnomad4 AFR exome AF: 0.0775

Gnomad4 AMR exome AF: 0.0463

Gnomad4 ASJ exome AF: 0.0662

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.0997

Gnomad4 NFE exome AF: 0.0622

Gnomad4 OTH exome AF: 0.0700

GnomAD4 genome AF: 0.0741 AC: 11226 AN: 151490 Hom.: 644 Cov.: 31 AF XY: 0.0756 AC XY: 5596 AN XY: 73976

Gnomad4 AFR AF: 0.0786

Gnomad4 AMR AF: 0.0428

Gnomad4 ASJ AF: 0.0657

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0655

Gnomad4 OTH AF: 0.0687

Alfa AF: 0.0719 Hom.: 107

Bravo AF: 0.0686

Asia WGS AF: 0.104 AC: 359 AN: 3430

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.5
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs8192726; hg19: chr19-41354496; COSMIC: COSV56534383; COSMIC: COSV56534383;