10-94849995-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000769.4(CYP2C19):c.1228C>T(p.Arg410Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00088 in 1,613,698 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0047 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 8 hom. )

Consequence

CYP2C19
NM_000769.4 missense

Scores

Clinical Significance

drug response practice guideline O:1

Conservation

PhyloP100: 0.298

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:

ENSG00000276490 (HGNC:):

ENSG00000276490 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012154967).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00467 (710/152196) while in subpopulation AFR AF= 0.0165 (687/41538). AF 95% confidence interval is 0.0155. There are 3 homozygotes in gnomad4. There are 343 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 710 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.1228C>T	p.Arg410Cys	missense_variant	Exon 8 of 9	ENST00000371321.9	NP_000760.1	P33261

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2C19	ENST00000371321.9 link	c.1228C>T	p.Arg410Cys	missense_variant	Exon 8 of 9	1	NM_000769.4	ENSP00000360372.3	P33261
ENSG00000276490	ENST00000464755.1 link	n.*986C>T		non_coding_transcript_exon_variant	Exon 13 of 14	2		ENSP00000483243.1	A0A087X0B3
ENSG00000276490	ENST00000464755.1 link	n.*986C>T		3_prime_UTR_variant	Exon 13 of 14	2		ENSP00000483243.1	A0A087X0B3
CYP2C19	ENST00000645461.1 link	n.2139C>T		non_coding_transcript_exon_variant	Exon 6 of 7

Frequencies

GnomAD3 genomes

AF:

0.00460

AC:

699

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

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:

0.0000147

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00133

AC:

333

AN:

251230

Hom.:

AF XY:

0.00100

AC XY:

136

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.0182

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.00

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:

0.000653

GnomAD4 exome

AF:

0.000486

AC:

710

AN:

1461502

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

300

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.0170

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00467

AC:

710

AN:

152196

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

343

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0165

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.000923

Hom.:

Bravo

AF:

0.00544

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00152

AC:

184

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: practice guideline

LINK: link

Submissions by phenotype

CYP2C19: normal 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

0.082

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.89

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.073

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.93

REVEL

Benign

0.040

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.037

Vest4

0.26

MVP

0.22

MPC

0.010

ClinPred

0.040

GERP RS

0.24

gMVP

0.16

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