rs55752064

Positions:

• chr10-94762755-T-A
• chr10-94762755-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000769.4(CYP2C19):​c.50T>A​(p.Leu17His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L17P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05

Genes affected

CYP2C19 (HGNC:2621): (cytochrome P450 family 2 subfamily C member 19) 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 and is known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, omeprazole, diazepam and some barbiturates. Polymorphism within this gene is associated with variable ability to metabolize mephenytoin, known as the poor metabolizer and extensive metabolizer phenotypes. The gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.50T>A	p.Leu17His	missense_variant	1/9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9	c.50T>A	p.Leu17His	missense_variant	1/9	1	NM_000769.4	ENSP00000360372	P1
CYP2C19	ENST00000480405.2	c.50T>A	p.Leu17His	missense_variant	1/3	1		ENSP00000483847

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.077	T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.47	T;.
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.1	.;D
REVEL	Benign	0.27
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.012	D;D
Vest4		0.51
MutPred		0.57		Gain of disorder (P = 0.0472);Gain of disorder (P = 0.0472);
MVP		0.64
MPC		0.021
ClinPred		0.98	D
GERP RS		4.2
gMVP		0.31

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: rs55752064; hg19: chr10-96522512;