rs17882687

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000769.4(CYP2C19):c.55A>C(p.Ile19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,924 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★).

Frequency

Genomes: 𝑓 0.0058 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 11 hom. )

Consequence

CYP2C19
NM_000769.4 missense

Scores

Clinical Significance

drug response practice guideline B:1O:1

Conservation

PhyloP100: -0.464

Publications

34 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009020865).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00581 (885/152226) while in subpopulation AFR AF = 0.0192 (796/41556). AF 95% confidence interval is 0.0181. There are 13 homozygotes in GnomAd4. There are 425 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 885 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.55A>C	p.Ile19Leu	missense_variant	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.55A>C	p.Ile19Leu	missense_variant	Exon 1 of 9	1	NM_000769.4	ENSP00000360372.3	P33261
CYP2C19	ENST00000480405.2 link	c.55A>C	p.Ile19Leu	missense_variant	Exon 1 of 3	1		ENSP00000483847.1	A0A087X125
ENSG00000276490	ENST00000464755.1 link	n.932-12298A>C		intron_variant	Intron 6 of 13	2		ENSP00000483243.1	A0A087X0B3

Frequencies

GnomAD3 genomes

AF:

0.00573

AC:

872

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00176

AC:

443

AN:

251250

AF XY:

0.00137

show subpopulations

Gnomad AFR exome

AF:

0.0195

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00104

AC:

1520

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000970

AC XY:

705

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.0221

AC:

740

AN:

33470

American (AMR)

AF:

0.00103

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00436

AC:

114

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.000139

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000402

AC:

447

AN:

1111900

Other (OTH)

AF:

0.00230

AC:

139

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00581

AC:

885

AN:

152226

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

425

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0192

AC:

796

AN:

41556

American (AMR)

AF:

0.00222

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68020

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00329

Hom.:

Bravo

AF:

0.00674

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0195

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00213

AC:

258

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:1

Revision: practice guideline

LINK: link

Submissions by phenotype

not provided

Benign:1

May 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.058

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.17

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.0023

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.0092

T;.

MetaRNN

Benign

0.0090

T;T

MetaSVM

Benign

-0.94

PhyloP100

-0.46

PrimateAI

Benign

0.39

PROVEAN

Benign

1.4

.;N

REVEL

Benign

0.091

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Vest4

0.078

MVP

0.19

MPC

0.0054

ClinPred

0.0028

GERP RS

-4.0

PromoterAI

0.029

Neutral

(source)

gMVP

0.094

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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