19-41088545-G-C

Variant names:

• chr19-41088545-G-C
• rs8192784
• NM_000766.5:c.74G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000766.5(CYP2A13):​c.74G>C​(p.Arg25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYP2A13 NM_000766.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.728
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28386554).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000766.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A13	NM_000766.5	MANE Select	c.74G>C	p.Arg25Pro	missense	Exon 1 of 9	NP_000757.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A13	ENST00000330436.4	TSL:1 MANE Select	c.74G>C	p.Arg25Pro	missense	Exon 1 of 9	ENSP00000332679.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111866

Other (OTH) AF: 0.0000331 AC: 2 AN: 60380

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.73
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.035	D
Polyphen		0.74	P
Vest4		0.40
MutPred		0.54		Loss of MoRF binding (P = 0.0021)
MVP		0.73
MPC		0.33
ClinPred		0.95	D
GERP RS		1.1
PromoterAI		0.0050	Neutral
Varity_R		0.47
gMVP		0.50
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs8192784; hg19: chr19-41594450;