chr10-94775165-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000769.4(CYP2C19):c.276G>C(p.Glu92Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,614,098 control chromosomes in the GnomAD database, including 763 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.022 ( 46 hom., cov: 32)

Exomes 𝑓: 0.029 ( 717 hom. )

Consequence

CYP2C19
NM_000769.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.10

Publications

51 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004840821).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0218 (3315/152236) while in subpopulation NFE AF = 0.0316 (2146/68012). AF 95% confidence interval is 0.0304. There are 46 homozygotes in GnomAd4. There are 1560 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3315 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000769.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	NM_000769.4	MANE Select	c.276G>C	p.Glu92Asp	missense	Exon 2 of 9	NP_000760.1	P33261

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP2C19	ENST00000371321.9	TSL:1 MANE Select	c.276G>C	p.Glu92Asp	missense	Exon 2 of 9	ENSP00000360372.3	P33261
CYP2C19	ENST00000480405.2	TSL:1	c.276G>C	p.Glu92Asp	missense	Exon 2 of 3	ENSP00000483847.1	A0A087X125
ENSG00000276490	ENST00000464755.1	TSL:2	n.*34G>C		non_coding_transcript_exon	Exon 7 of 14	ENSP00000483243.1	A0A087X0B3

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3317

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00840

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00848

Gnomad FIN

AF:

0.0398

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0315

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0226

AC:

5675

AN:

251482

AF XY:

0.0227

show subpopulations

Gnomad AFR exome

AF:

0.00787

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.00655

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0382

Gnomad NFE exome

AF:

0.0327

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0289

AC:

42253

AN:

1461862

Hom.:

717

Cov.:

AF XY:

0.0283

AC XY:

20580

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00672

AC:

225

AN:

33480

American (AMR)

AF:

0.0153

AC:

685

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00828

AC:

714

AN:

86258

European-Finnish (FIN)

AF:

0.0398

AC:

2124

AN:

53398

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0330

AC:

36747

AN:

1112004

Other (OTH)

AF:

0.0248

AC:

1499

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

2589

5177

7766

10354

12943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1372

2744

4116

5488

6860

<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:

0.0218

AC:

3315

AN:

152236

Hom.:

Cov.:

AF XY:

0.0210

AC XY:

1560

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00837

AC:

348

AN:

41562

American (AMR)

AF:

0.0164

AC:

251

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00849

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0398

AC:

420

AN:

10564

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0316

AC:

2146

AN:

68012

Other (OTH)

AF:

0.0175

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

177

354

530

707

884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0218

Hom.:

Bravo

AF:

0.0200

TwinsUK

AF:

0.0326

AC:

121

ALSPAC

AF:

0.0291

AC:

112

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.0305

AC:

262

ExAC

AF:

0.0236

AC:

2865

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0303

EpiControl

AF:

0.0335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.49

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.025

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0048

MetaSVM

Benign

-1.1

PhyloP100

-4.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.1

REVEL

Benign

0.097

Sift

Benign

0.42

Sift4G

Benign

0.34

Vest4

0.057

MutPred

0.58

Loss of disorder (P = 0.1562)

MPC

0.0057

ClinPred

0.0089

GERP RS

-5.0

gMVP

0.24

Mutation Taster

=85/15

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over