rs6413474

Positions:

• chr19-40843854-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_000762.6(CYP2A6):​c.1427A>G​(p.Lys476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,611,382 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (21 hom., cov: 30)
  • Exomes 𝑓: 0.013 (135 hom.)
• Consequence: CYP2A6 NM_000762.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.402

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]

ENSG00000268797 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP5: Variant 19-40843854-T-C is Pathogenic according to our data. Variant chr19-40843854-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036874413). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0132 (19269/1460556) while in subpopulation SAS AF= 0.0202 (1737/86146). AF 95% confidence interval is 0.0194. There are 135 homozygotes in gnomad4_exome. There are 9832 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1575 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2A6	NM_000762.6	c.1427A>G	p.Lys476Arg	missense_variant	9/9	ENST00000301141.10	NP_000753.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2A6	ENST00000301141.10	c.1427A>G	p.Lys476Arg	missense_variant	9/9	1	NM_000762.6	ENSP00000301141.4
ENSG00000268797	ENST00000601627.1	n.117+42439T>C		intron_variant		3		ENSP00000469533.1
CYP2A6	ENST00000599960.1	n.346A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1575 AN: 150708 Hom.: 21 Cov.: 30

Gnomad AFR AF: 0.00313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00702

Gnomad ASJ AF: 0.0324

Gnomad EAS AF: 0.000608

Gnomad SAS AF: 0.0142

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0140

GnomAD3 exomes AF: 0.0122 AC: 3055 AN: 250690 Hom.: 27 AF XY: 0.0134 AC XY: 1813 AN XY: 135500

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0188

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0132 AC: 19269 AN: 1460556 Hom.: 135 Cov.: 33 AF XY: 0.0135 AC XY: 9832 AN XY: 726606

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00512

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.0202

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0104 AC: 1575 AN: 150826 Hom.: 21 Cov.: 30 AF XY: 0.0111 AC XY: 820 AN XY: 73608

Gnomad4 AFR AF: 0.00312

Gnomad4 AMR AF: 0.00701

Gnomad4 ASJ AF: 0.0324

Gnomad4 EAS AF: 0.000610

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0256

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0139

Alfa AF: 0.0151 Hom.: 3

Bravo AF: 0.00855

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0115 AC: 1401

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.86
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.025
Sift	Benign	0.50	T
Sift4G	Benign	0.53	T
Vest4		0.037
MPC		1.6
ClinPred		0.0012	T
GERP RS		0.73
gMVP		0.37

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: rs6413474; hg19: chr19-41349759;