rs4986893

Variant names:

Your query was ambiguous. Multiple possible variants found:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . 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 involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.00294 (AC=4,750) in the gnomAD database across 1,613,588 control chromosomes, including 214 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0898. In-silico predictor (BayesDel (addAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★★★).

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

688 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

new If you want to explore the variant's impact on the transcript NM_000769.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.0898 — exceeds 5%% threshold (BA1 applied)

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.636G>A	p.Trp212*	stop_gained	Exon 4 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.636G>A	p.Trp212*	stop_gained	Exon 4 of 9	ENSP00000360372.3	P33261
ENSG00000276490	ENST00000464755.1	TSL:2	n.*394G>A		3_prime_UTR	Exon 9 of 14	ENSP00000483243.1	A0A087X0B3
ENSG00000276490	ENST00000464755.1	TSL:2	n.*394G>A		non_coding_transcript_exon	Exon 9 of 14	ENSP00000483243.1	A0A087X0B3

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

Asia WGS

AF:

0.0460

AC:

160

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.129

AC:

15833

AN:

122712

Turkish Variome

AF:

0.00357

AC:

AN:

6722

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0501

AC:

449

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.00342

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:drug response

Revision:practice guideline

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Acute coronary syndrome (1)

Clopidogrel response (1)

CYP2C19: no function (1)

MEPHENYTOIN, POOR METABOLISM OF (1)

PROGUANIL, POOR METABOLISM OF (1)

Computational scores

Source: dbNSFP v4.9

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

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over