rs8192720

Positions:

• chr19-40850405-G-A
• chr19-40850405-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000762.6(CYP2A6):​c.22C>T​(p.Leu8=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,609,772 control chromosomes in the GnomAD database, including 2,390 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 0.019 (244 hom., cov: 31)
  • Exomes 𝑓: 0.011 (2146 hom.)
• Consequence: CYP2A6 NM_000762.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-40850405-G-A is Benign according to our data. Variant chr19-40850405-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.22C>T	p.Leu8=	synonymous_variant	1/9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.22C>T	p.Leu8=	synonymous_variant	1/9	1	NM_000762.6	ENSP00000301141	P1
CYP2A6	ENST00000596719.5	n.36C>T		non_coding_transcript_exon_variant	1/6	1
CYP2A6	ENST00000600495.1	c.22C>T	p.Leu8=	synonymous_variant, NMD_transcript_variant	1/6	1		ENSP00000472905

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2849 AN: 151164 Hom.: 244 Cov.: 31

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.0191

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.0193

GnomAD3 exomes AF: 0.0227 AC: 5675 AN: 250066 Hom.: 711 AF XY: 0.0210 AC XY: 2831 AN XY: 135128

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.00432

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.191

Gnomad SAS exome AF: 0.00427

Gnomad FIN exome AF: 0.0338

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.0146

GnomAD4 exome AF: 0.0111 AC: 16203 AN: 1458496 Hom.: 2146 Cov.: 34 AF XY: 0.0110 AC XY: 7958 AN XY: 725560

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.00464

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.00475

Gnomad4 FIN exome AF: 0.0324

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0188 AC: 2848 AN: 151276 Hom.: 244 Cov.: 31 AF XY: 0.0206 AC XY: 1523 AN XY: 73864

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00679

Gnomad4 ASJ AF: 0.0191

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.00989

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.00318

Gnomad4 OTH AF: 0.0192

Alfa AF: 0.00930 Hom.: 35

Bravo AF: 0.0190

Asia WGS AF: 0.0890 AC: 303 AN: 3428

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.1
DANN	Benign	0.62

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: rs8192720; hg19: chr19-41356310; COSMIC: COSV56534090;