10-94762755-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000769.4(CYP2C19):c.50T>C(p.Leu17Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: drug response practice guideline O:1
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C19	NM_000769.4	c.50T>C	p.Leu17Pro	missense_variant	1/9	ENST00000371321.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C19	ENST00000371321.9	c.50T>C	p.Leu17Pro	missense_variant	1/9	1	NM_000769.4	P1
CYP2C19	ENST00000480405.2	c.50T>C	p.Leu17Pro	missense_variant	1/3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461708 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: practice guideline

Submissions by phenotype

CYP2C19: uncertain function Other:1

drug response, practice guideline

curation

Clinical Pharmacogenetics Implementation Consortium

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- Allele function

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.42	T;.
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.017	D;D
Vest4		0.75
MutPred		0.83		Loss of stability (P = 0.0507);Loss of stability (P = 0.0507);
MVP		0.57
MPC		0.0050
ClinPred		0.43	T
GERP RS		4.2
gMVP		0.32

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;