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rs4986893

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4BP6_StrongBA1

The NM_000769(CYP2C19):c.636G>A(p.Trp212Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00251 in 152056 control chromosomes in the gnomAD Genomes database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (β˜…β˜…β˜…β˜…). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0025 ( 11 hom., cov: 32)
Exomes 𝑓: 0.0054 ( 40 hom. )

Consequence

CYP2C19
NM_000769 stop_gained

Scores

1
1
5

Clinical Significance

drug response practice guideline B:1O:5

Conservation

PhyloP100: 4.14

Links

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM4
?
Stoplost variant in NM_000769 Downstream stopcodon found after 498 codons.
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: {other=1, drug_response=1, Benign=1}. Variant chr10-94780653-G-A is described in Lovd as [Benign]. Variant chr10-94780653-G-A is described in Lovd as [Pathogenic].
BA1
?
GnomAd highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP2C19NM_000769.4 linkuse as main transcriptc.636G>A p.Trp212Ter stop_gained 4/9 ENST00000371321.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP2C19ENST00000371321.9 linkuse as main transcriptc.636G>A p.Trp212Ter stop_gained 4/91 NM_000769.4 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
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
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
36
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

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;