rs28399504

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PVS1_SupportingBS2

The NM_000769.4(CYP2C19):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,130 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 14 hom. )

Consequence

CYP2C19
NM_000769.4 start_lost

Scores

Clinical Significance

drug response practice guideline B:1O:3

Conservation

PhyloP100: 0.495

Publications

182 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: Likely_benign. The variant received -3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 74 codons. Genomic position: 94775109. Lost 0.149 part of the original CDS.

BS2

High AC in GnomAd4 at 362 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 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.1A>G	p.Met1?	start_lost	Exon 1 of 9	1	NM_000769.4	ENSP00000360372.3	P33261
CYP2C19	ENST00000480405.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	1		ENSP00000483847.1	A0A087X125
ENSG00000276490	ENST00000464755.1 link	n.932-12352A>G		intron_variant	Intron 6 of 13	2		ENSP00000483243.1	A0A087X0B3

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

362

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00647

Gnomad ASJ

AF:

0.0158

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00233

AC:

585

AN:

251032

AF XY:

0.00226

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00287

Gnomad ASJ exome

AF:

0.0162

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00251

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00240

AC:

3504

AN:

1460850

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1769

AN XY:

726674

show subpopulations

African (AFR)

AF:

0.000419

AC:

AN:

33450

American (AMR)

AF:

0.00286

AC:

128

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

428

AN:

26092

East Asian (EAS)

AF:

0.000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.000290

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00110

AC:

AN:

5464

European-Non Finnish (NFE)

AF:

0.00244

AC:

2712

AN:

1111568

Other (OTH)

AF:

0.00295

AC:

178

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

170

339

509

678

848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00238

AC:

362

AN:

152280

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41588

American (AMR)

AF:

0.00647

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00256

AC:

174

AN:

68018

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00286

Hom.:

Bravo

AF:

0.00247

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00189

AC:

229

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00279

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:3

Revision: practice guideline

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Mar 26, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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).

Mephenytoin, poor metabolism of

Other:1

Jan 01, 1998

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.062

T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.90

D;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.70

PhyloP100

0.49

PROVEAN

Uncertain

-3.4

.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.016

D;D

Vest4

0.49

MVP

0.61

ClinPred

0.060

GERP RS

1.8

PromoterAI

0.047

Neutral

(source)

gMVP

0.33

Mutation Taster

=114/86

polymorphism

(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