rs4986893

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000769.4(CYP2C19):c.636G>A(p.Trp212*) 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:6

Conservation

PhyloP100: 4.14

Publications

673 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

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 rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.636G>A	p.Trp212*	stop_gained	Exon 4 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.636G>A	p.Trp212*	stop_gained	Exon 4 of 9	1	NM_000769.4	ENSP00000360372.3	P33261
ENSG00000276490	ENST00000464755.1 link	n.*394G>A		non_coding_transcript_exon_variant	Exon 9 of 14	2		ENSP00000483243.1	A0A087X0B3
ENSG00000276490	ENST00000464755.1 link	n.*394G>A		3_prime_UTR_variant	Exon 9 of 14	2		ENSP00000483243.1	A0A087X0B3
CYP2C19	ENST00000645461.1 link	n.1689G>A		non_coding_transcript_exon_variant	Exon 3 of 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

GnomAD2 exomes

AF:

0.00538

AC:

1351

AN:

251142

AF XY:

0.00507

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 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

African (AFR)

AF:

0.000538

AC:

AN:

33442

American (AMR)

AF:

0.000179

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0923

AC:

3662

AN:

39672

South Asian (SAS)

AF:

0.00340

AC:

293

AN:

86240

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000101

AC:

112

AN:

1111770

Other (OTH)

AF:

0.00421

AC:

254

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

202

404

606

808

1010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00255

AC:

388

AN:

152176

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41550

American (AMR)

AF:

0.000523

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0610

AC:

315

AN:

5168

South Asian (SAS)

AF:

0.00498

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68004

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00555

Hom.:

875

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:6

Revision: practice guideline

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Aug 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22865819, 20549256, 21855977, 22344438, 25087612, 25525159, 23874401, 7969038, 24906606) -

Dec 28, 2015

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Proguanil, poor metabolism of

Other:1

Jun 01, 2009

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mephenytoin, poor metabolism of

Other:1

Jun 01, 2009

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Acute coronary syndrome

Other:1

Cardiology Department, The First Affiliated Hospital of Nanjing Medical University

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

- decreased function

Clopidogrel response

Other:1

Faculty of Pharmacy, Damascus University

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

rs4986893 is a SNP in the CYP2C19 gene and is linked to poor clopidogrel metabolic activation. rs4986893 is associated with reduced enzyme activity of CYP2C19 and lower concentration of clopidogrel active metabolite. likely responsive

CYP2C19: no 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

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Benign

0.18

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.052

PhyloP100

4.1

Vest4

0.79

GERP RS

3.3

Mutation Taster

=145/55

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over