rs4986893

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_StrongBA1

The NM_000769.4(CYP2C19):​c.636G>A​(p.Trp212Ter) 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

1
1
5

Clinical Significance

drug response practice guideline B:1O:5

Conservation

PhyloP100: 4.14
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6
Variant 10-94780653-G-A is Benign according to our data. Variant chr10-94780653-G-A is described in ClinVar as [drug_response]. Clinvar id is 16899.Status of the report is practice_guideline, 4 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=1, Benign=1, other=1}. Variant chr10-94780653-G-A is described in Lovd as [Benign]. Variant chr10-94780653-G-A is described in Lovd as [Pathogenic].
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/exons MANE Protein UniProt
CYP2C19NM_000769.4 linkuse as main transcriptc.636G>A p.Trp212Ter stop_gained 4/9 ENST00000371321.9 NP_000760.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP2C19ENST00000371321.9 linkuse as main transcriptc.636G>A p.Trp212Ter stop_gained 4/91 NM_000769.4 ENSP00000360372 P1
CYP2C19ENST00000645461.1 linkuse as main transcriptn.1689G>A non_coding_transcript_exon_variant 3/7

Frequencies

GnomAD3 genomes
AF:
0.00251
AC:
381
AN:
152056
Hom.:
11
Cov.:
32
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
GnomAD3 exomes
AF:
0.00538
AC:
1351
AN:
251142
Hom.:
40
AF XY:
0.00507
AC XY:
688
AN XY:
135770
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 SAS exome
AF:
0.00399
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.:
31
AF XY:
0.00303
AC XY:
2204
AN XY:
727026
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0923
Gnomad4 SAS exome
AF:
0.00340
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.000101
Gnomad4 OTH exome
AF:
0.00421
GnomAD4 genome
AF:
0.00255
AC:
388
AN:
152176
Hom.:
13
Cov.:
32
AF XY:
0.00273
AC XY:
203
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.000385
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0610
Gnomad4 SAS
AF:
0.00498
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00614
Alfa
AF:
0.00722
Hom.:
873
Bravo
AF:
0.00267
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000233
AC:
2
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:5
Revision: practice guideline
LINK: link

Submissions by phenotype

not provided Benign:1Other:1
other, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 28, 2015- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitterclinical testingGeneDxAug 06, 2018This variant is associated with the following publications: (PMID: 22865819, 20549256, 21855977, 22344438, 25087612, 25525159, 23874401, 7969038, 24906606) -
Proguanil, poor metabolism of Other:1
drug response, no assertion criteria providedliterature onlyOMIMJun 01, 2009- -
Mephenytoin, poor metabolism of Other:1
drug response, no assertion criteria providedliterature onlyOMIMJun 01, 2009- -
Acute coronary syndrome Other:1
drug response, no assertion criteria providedresearchCardiology Department, The First Affiliated Hospital of Nanjing Medical University-- decreased function
CYP2C19: no function Other:1
drug response, practice guidelinecurationClinical Pharmacogenetics Implementation Consortium-- Allele function

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
35
DANN
Uncertain
0.98
Eigen
Benign
0.18
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.052
N
MutationTaster
Benign
1.0
A
Vest4
0.79
GERP RS
3.3

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4986893; hg19: chr10-96540410; COSMIC: COSV64907205; COSMIC: COSV64907205; API