chr10-94775489-G-C

Position:

• chr10-94775489-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000769.4(CYP2C19):​c.431G>C​(p.Arg144Pro) 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. 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. R144H) 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: 3.83

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-94775489-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.431G>C	p.Arg144Pro	missense_variant	3/9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9	c.431G>C	p.Arg144Pro	missense_variant	3/9	1	NM_000769.4	ENSP00000360372.3
ENSG00000276490	ENST00000464755.1	n.*189G>C		non_coding_transcript_exon_variant	8/14	2		ENSP00000483243.1
ENSG00000276490	ENST00000464755.1	n.*189G>C		3_prime_UTR_variant	8/14	2		ENSP00000483243.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.095
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.81	T;.
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	-0.26	T
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-6.2	.;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.54
MutPred		0.71		Loss of MoRF binding (P = 0.0222);Loss of MoRF binding (P = 0.0222);
MVP		0.79
MPC		0.022
ClinPred		1.0	D
GERP RS		3.0
gMVP		0.68

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: rs17884712; hg19: chr10-96535246;