10-94762788-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000769.4(CYP2C19):c.83A>T(p.Lys28Ile) 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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: drug response practice guideline O:1
• Conservation: PhyloP100: 0.854

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23988187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C19	NM_000769.4	c.83A>T	p.Lys28Ile	missense_variant	1/9	ENST00000371321.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C19	ENST00000371321.9	c.83A>T	p.Lys28Ile	missense_variant	1/9	1	NM_000769.4	P1
CYP2C19	ENST00000480405.2	c.83A>T	p.Lys28Ile	missense_variant	1/3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

-

- Allele function

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.090	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.71	T;.
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.0030	D;D
Vest4		0.39
MutPred		0.44		Loss of methylation at K28 (P = 2e-04);Loss of methylation at K28 (P = 2e-04);
MVP		0.40
MPC		0.0057
ClinPred		0.72	D
GERP RS		1.7
gMVP		0.27

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: rs1564656981; hg19: chr10-96522545;