NM_000769.4:c.232C>T

Variant names:

• chr10-94775121-C-T
• rs1564660997
• NM_000769.4:c.232C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000769.4(CYP2C19):​c.232C>T​(p.His78Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: drug response practice guideline O:1
• Conservation: PhyloP100: -0.268

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]

ENSG00000276490 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26517743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.232C>T	p.His78Tyr	missense_variant	Exon 2 of 9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9	c.232C>T	p.His78Tyr	missense_variant	Exon 2 of 9	1	NM_000769.4	ENSP00000360372.3
CYP2C19	ENST00000480405.2	c.232C>T	p.His78Tyr	missense_variant	Exon 2 of 3	1		ENSP00000483847.1
ENSG00000276490	ENST00000464755.1	n.995C>T		non_coding_transcript_exon_variant	Exon 7 of 14	2		ENSP00000483243.1
CYP2C19	ENST00000645461.1	n.1285C>T		non_coding_transcript_exon_variant	Exon 1 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: practice guideline

Submissions by phenotype

CYP2C19: uncertain function Other:1

-

Clinical Pharmacogenetics Implementation Consortium

Significance: drug response

Review Status: practice guideline

Collection Method: curation

- Allele function

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.7
DANN	Benign	0.62
DEOGEN2	Benign	0.088	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.83	T;.
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.4	.;D
REVEL	Benign	0.062
Sift	Benign	0.11	.;T
Sift4G	Benign	1.0	T;T
Vest4		0.10
MutPred		0.70		Loss of catalytic residue at G79 (P = 0.1258);Loss of catalytic residue at G79 (P = 0.1258);
MVP		0.13
MPC		0.0066
ClinPred		0.084	T
GERP RS		-0.49
gMVP		0.25

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: rs1564660997; hg19: chr10-96534878;