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rs4244285

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000769.4(CYP2C19):c.681G>A(p.Pro227=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,464,646 control chromosomes in the GnomAD database, including 20,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Synonymous variant affecting the same amino acid position (i.e. P227P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.17 ( 2363 hom., cov: 32)
Exomes 𝑓: 0.16 ( 18379 hom. )

Consequence

CYP2C19
NM_000769.4 synonymous

Scores

2

Clinical Significance

Likely benign; other criteria provided, multiple submitters, no conflicts B:1O:4

Conservation

PhyloP100: -0.801
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 -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP7
Synonymous conserved (PhyloP=-0.801 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP2C19NM_000769.4 linkuse as main transcriptc.681G>A p.Pro227= synonymous_variant 5/9 ENST00000371321.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP2C19ENST00000371321.9 linkuse as main transcriptc.681G>A p.Pro227= synonymous_variant 5/91 NM_000769.4 P1
CYP2C19ENST00000645461.1 linkuse as main transcriptn.1734G>A non_coding_transcript_exon_variant 4/7

Frequencies

GnomAD3 genomes
AF:
0.168
AC:
25424
AN:
151376
Hom.:
2358
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.177
Gnomad AMI
AF:
0.182
Gnomad AMR
AF:
0.130
Gnomad ASJ
AF:
0.132
Gnomad EAS
AF:
0.312
Gnomad SAS
AF:
0.331
Gnomad FIN
AF:
0.186
Gnomad MID
AF:
0.0865
Gnomad NFE
AF:
0.148
Gnomad OTH
AF:
0.149
GnomAD3 exomes
AF:
0.176
AC:
28518
AN:
161670
Hom.:
2972
AF XY:
0.181
AC XY:
16382
AN XY:
90276
show subpopulations
Gnomad AFR exome
AF:
0.176
Gnomad AMR exome
AF:
0.0991
Gnomad ASJ exome
AF:
0.130
Gnomad EAS exome
AF:
0.307
Gnomad SAS exome
AF:
0.324
Gnomad FIN exome
AF:
0.174
Gnomad NFE exome
AF:
0.147
Gnomad OTH exome
AF:
0.153
GnomAD4 exome
AF:
0.159
AC:
209244
AN:
1313152
Hom.:
18379
Cov.:
28
AF XY:
0.163
AC XY:
105482
AN XY:
648108
show subpopulations
Gnomad4 AFR exome
AF:
0.180
Gnomad4 AMR exome
AF:
0.104
Gnomad4 ASJ exome
AF:
0.132
Gnomad4 EAS exome
AF:
0.302
Gnomad4 SAS exome
AF:
0.319
Gnomad4 FIN exome
AF:
0.173
Gnomad4 NFE exome
AF:
0.146
Gnomad4 OTH exome
AF:
0.164
GnomAD4 genome
AF:
0.168
AC:
25442
AN:
151494
Hom.:
2363
Cov.:
32
AF XY:
0.172
AC XY:
12754
AN XY:
73968
show subpopulations
Gnomad4 AFR
AF:
0.177
Gnomad4 AMR
AF:
0.130
Gnomad4 ASJ
AF:
0.132
Gnomad4 EAS
AF:
0.312
Gnomad4 SAS
AF:
0.332
Gnomad4 FIN
AF:
0.186
Gnomad4 NFE
AF:
0.148
Gnomad4 OTH
AF:
0.153
Alfa
AF:
0.150
Hom.:
3297
Bravo
AF:
0.160
Asia WGS
AF:
0.302
AC:
1046
AN:
3474

ClinVar

Significance: Likely benign; other
Submissions summary: Benign:1Other:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 09, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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- -
not provided Other:1
other, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 07, 2018- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Clopidogrel response Other:1
drug response, no assertion criteria providedliterature onlyOMIMMay 14, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
Cadd
Benign
16
Dann
Benign
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.99
Position offset: 2
DS_AL_spliceai
0.89
Position offset: -38

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: rs4244285; hg19: chr10-96541616; COSMIC: COSV64906812; API