chr19-41091846-C-T

Position:

• chr19-41091846-C-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.769C>T​(p.Arg257Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,614,062 control chromosomes in the GnomAD database, including 1,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 (639 hom., cov: 31)
  • Exomes 𝑓: 0.019 (869 hom.)
• Consequence: CYP2A13 NM_000766.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.398

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=0.0015957355).
• BP6: Variant 19-41091846-C-T is Benign according to our data. Variant chr19-41091846-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2A13	NM_000766.5	c.769C>T	p.Arg257Cys	missense_variant	5/9	ENST00000330436.4	NP_000757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2A13	ENST00000330436.4	c.769C>T	p.Arg257Cys	missense_variant	5/9	1	NM_000766.5	ENSP00000332679	P1

Frequencies

GnomAD3 genomes AF: 0.0613 AC: 9332 AN: 152114 Hom.: 636 Cov.: 31

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.0734

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.00762

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0517

GnomAD3 exomes AF: 0.0312 AC: 7854 AN: 251488 Hom.: 343 AF XY: 0.0290 AC XY: 3948 AN XY: 135918

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0574

Gnomad EAS exome AF: 0.0720

Gnomad SAS exome AF: 0.0325

Gnomad FIN exome AF: 0.00790

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0191 AC: 27856 AN: 1461830 Hom.: 869 Cov.: 31 AF XY: 0.0190 AC XY: 13805 AN XY: 727222

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0565

Gnomad4 EAS exome AF: 0.0716

Gnomad4 SAS exome AF: 0.0294

Gnomad4 FIN exome AF: 0.00775

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.0325

GnomAD4 genome AF: 0.0615 AC: 9358 AN: 152232 Hom.: 639 Cov.: 31 AF XY: 0.0605 AC XY: 4504 AN XY: 74428

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0337

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.0737

Gnomad4 SAS AF: 0.0327

Gnomad4 FIN AF: 0.00762

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0307 Hom.: 131

Bravo AF: 0.0675

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.159 AC: 699

ESP6500EA AF: 0.0138 AC: 119

ExAC AF: 0.0341 AC: 4146

Asia WGS AF: 0.0560 AC: 195 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0132

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.093
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		0.068	B
Vest4		0.081
MPC		0.14
ClinPred		0.026	T
GERP RS		0.62
Varity_R		0.44
gMVP		0.41

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: rs8192789; hg19: chr19-41597751; COSMIC: COSV57837193;