chr10-94775489-G-A

Position:

chr10-94775489-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_StrongBS2

The ENST00000371321.9(CYP2C19):c.431G>A(p.Arg144His) variant causes a missense change. The variant allele was found at a frequency of 0.000707 in 1,614,010 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 5 hom. )

Consequence

CYP2C19
ENST00000371321.9 missense

Scores

Clinical Significance

drug response practice guideline B:1O:1

Conservation

PhyloP100: 3.83

Variant links:

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]

CYP2C19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008557826).

BP6

Variant 10-94775489-G-A is Benign according to our data. Variant chr10-94775489-G-A is described in ClinVar as [drug_response]. Clinvar id is 39352.Status of the report is practice_guideline, 4 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, drug_response=1}. Variant chr10-94775489-G-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd4 at 549 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C19	NM_000769.4 linkuse as main transcript	c.431G>A	p.Arg144His	missense_variant	3/9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CYP2C19	ENST00000371321.9 linkuse as main transcript	c.431G>A	p.Arg144His	missense_variant	3/9	1	NM_000769.4	ENSP00000360372	P1
CYP2C19	ENST00000480405.2 linkuse as main transcript	c.431G>A	p.Arg144His	missense_variant	3/3	1		ENSP00000483847
CYP2C19	ENST00000645461.1 linkuse as main transcript	n.1484G>A		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes

AF:

0.00357

AC:

543

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000891

AC:

224

AN:

251418

Hom.:

AF XY:

0.000633

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.0118

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000405

AC:

592

AN:

1461778

Hom.:

Cov.:

AF XY:

0.000327

AC XY:

238

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0136

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00361

AC:

549

AN:

152232

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0126

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00194

Hom.:

Bravo

AF:

0.00432

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00108

AC:

131

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:1

Revision: practice guideline

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2018

This variant is associated with the following publications: (PMID: 21325430, 12464799) -

CYP2C19: decreased 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

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.072

T;.

Eigen

Benign

0.045

Eigen_PC

Benign

-0.083

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.81

T;.

MetaRNN

Benign

0.0086

T;T

MetaSVM

Benign

-0.76

MutationTaster

Benign

0.98

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-4.4

.;D

REVEL

Benign

0.28

Sift

Uncertain

0.0080

.;D

Sift4G

Uncertain

0.039

D;D

Vest4

0.13

MVP

0.73

MPC

0.019

ClinPred

0.064

GERP RS

3.0

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over