rs4986893

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4BP6_StrongBA1

The NM_000769.4(CYP2C19):c.636G>A(p.Trp212Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00294 in 1,613,588 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0025 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 201 hom. )

Consequence

CYP2C19
NM_000769.4 stop_gained

Scores

Clinical Significance

drug response practice guideline B:1O:5

Conservation

PhyloP100: 4.14

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 -10 ACMG points.

PM4

Stoplost variant in NM_000769.4 Downstream stopcodon found after 498 codons.

BP6

Variant 10-94780653-G-A is Benign according to our data. Variant chr10-94780653-G-A is described in ClinVar as [drug_response]. Clinvar id is 16899.Status of the report is practice_guideline, 4 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=1, other=1, Benign=1}. Variant chr10-94780653-G-A is described in Lovd as [Benign]. Variant chr10-94780653-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C19	NM_000769.4 linkuse as main transcript	c.636G>A	p.Trp212Ter	stop_gained	4/9	ENST00000371321.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C19	ENST00000371321.9 linkuse as main transcript	c.636G>A	p.Trp212Ter	stop_gained	4/9	1	NM_000769.4	P1
CYP2C19	ENST00000645461.1 linkuse as main transcript	n.1689G>A		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes

AF:

0.00251

AC:

381

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0610

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00538

AC:

1351

AN:

251142

Hom.:

AF XY:

0.00507

AC XY:

688

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0636

Gnomad SAS exome

AF:

0.00399

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00298

AC:

4362

AN:

1461412

Hom.:

201

Cov.:

AF XY:

0.00303

AC XY:

2204

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0923

Gnomad4 SAS exome

AF:

0.00340

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.00421

GnomAD4 genome

AF:

0.00255

AC:

388

AN:

152176

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0610

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00722

Hom.:

873

Bravo

AF:

0.00267

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00549

AC:

667

Asia WGS

AF:

0.0460

AC:

160

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:5

Revision: practice guideline

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2015	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	This variant is associated with the following publications: (PMID: 22865819, 20549256, 21855977, 22344438, 25087612, 25525159, 23874401, 7969038, 24906606) -

Proguanil, poor metabolism of

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Mephenytoin, poor metabolism of

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Acute coronary syndrome

Other:1

drug response, no assertion criteria provided

research

Cardiology Department, The First Affiliated Hospital of Nanjing Medical University

- decreased function

CYP2C19: no 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

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Pathogenic

0.24

Cadd

Pathogenic

Dann

Uncertain

0.98

Eigen

Benign

0.18

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.052

MutationTaster

Benign

1.0

Vest4

0.79

GERP RS

3.3

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