rs8192784

Positions:

• chr19-41088545-G-A
• chr19-41088545-G-T

Variant summary

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

The NM_000766.5(CYP2A13):​c.74G>A​(p.Arg25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,613,868 control chromosomes in the GnomAD database, including 1,551 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.061 (641 hom., cov: 31)
  • Exomes 𝑓: 0.019 (910 hom.)
• Consequence: CYP2A13 NM_000766.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.728

Genes affected

CYP2A13 (HGNC:2608): (cytochrome P450 family 2 subfamily A member 13) This gene 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. Although its endogenous substrate has not been determined, it is known to metabolize 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a major nitrosamine specific to tobacco. This gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013855398).
• BP6: Variant 19-41088545-G-A is Benign according to our data. Variant chr19-41088545-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2A13	NM_000766.5	c.74G>A	p.Arg25Gln	missense_variant	1/9	ENST00000330436.4	NP_000757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2A13	ENST00000330436.4	c.74G>A	p.Arg25Gln	missense_variant	1/9	1	NM_000766.5	ENSP00000332679	P1

Frequencies

GnomAD3 genomes AF: 0.0607 AC: 9227 AN: 152064 Hom.: 638 Cov.: 31

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.0735

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0517

GnomAD3 exomes AF: 0.0306 AC: 7688 AN: 251276 Hom.: 337 AF XY: 0.0284 AC XY: 3862 AN XY: 135812

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0575

Gnomad EAS exome AF: 0.0717

Gnomad SAS exome AF: 0.0321

Gnomad FIN exome AF: 0.00517

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0249

GnomAD4 exome AF: 0.0188 AC: 27543 AN: 1461686 Hom.: 910 Cov.: 32 AF XY: 0.0188 AC XY: 13659 AN XY: 727162

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.0170

Gnomad4 ASJ exome AF: 0.0568

Gnomad4 EAS exome AF: 0.0712

Gnomad4 SAS exome AF: 0.0291

Gnomad4 FIN exome AF: 0.00565

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.0322

GnomAD4 genome AF: 0.0608 AC: 9251 AN: 152182 Hom.: 641 Cov.: 31 AF XY: 0.0598 AC XY: 4446 AN XY: 74408

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.0335

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.0739

Gnomad4 SAS AF: 0.0330

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0512

Alfa AF: 0.0282 Hom.: 68

Bravo AF: 0.0668

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.147 AC: 648

ESP6500EA AF: 0.0140 AC: 120

ExAC AF: 0.0335 AC: 4062

EpiCase AF: 0.0142

EpiControl AF: 0.0131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.6
DANN	Benign	0.89
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.23	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.063
Sift	Benign	0.22	T
Sift4G	Benign	0.15	T
Polyphen		0.0030	B
Vest4		0.029
MPC		0.12
ClinPred		0.0015	T
GERP RS		1.1
Varity_R		0.041
gMVP		0.28

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: rs8192784; hg19: chr19-41594450; COSMIC: COSV57839158;