19-41090469-T-C

Variant names:

• chr19-41090469-T-C
• rs769429044
• NM_000766.5:c.559T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000766.5(CYP2A13):​c.559T>C​(p.Phe187Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP2A13 NM_000766.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A13	NM_000766.5	MANE Select	c.559T>C	p.Phe187Leu	missense	Exon 4 of 9	NP_000757.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2A13	ENST00000330436.4	TSL:1 MANE Select	c.559T>C	p.Phe187Leu	missense	Exon 4 of 9	ENSP00000332679.1	Q16696
	CYP2A13	ENST00000874269.1		c.559T>C	p.Phe187Leu	missense	Exon 4 of 9	ENSP00000544328.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.0048	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.065	T
Polyphen		0.24	B
Vest4		0.45
MutPred		0.88		Loss of helix (P = 0.1706)
MVP		0.78
MPC		0.13
ClinPred		0.96	D
GERP RS		3.7
Varity_R		0.86
gMVP		0.38
Mutation Taster		=45/55	disease causing

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: rs769429044; hg19: chr19-41596374;