chr10-94781859-G-A

Position:

chr10-94781859-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The ENST00000371321.9(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
ENST00000371321.9 synonymous

Scores

Clinical Significance

Likely benign; other criteria provided, multiple submitters, no conflicts B:2O:5

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]

CYP2C19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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	Protein	UniProt
CYP2C19	NM_000769.4 linkuse as main transcript	c.681G>A	p.Pro227=	synonymous_variant	5/9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9 linkuse as main transcript	c.681G>A	p.Pro227=	synonymous_variant	5/9	1	NM_000769.4	ENSP00000360372	P1
CYP2C19	ENST00000645461.1 linkuse as main transcript	n.1734G>A		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25424

AN:

151376

Hom.:

2358

Cov.:

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.:

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.:

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:2Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
other, criteria provided, single submitter	clinical testing	Eurofins 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:2

drug response, no assertion criteria provided	research	Faculty of Pharmacy, Damascus University	-	rs4244285 is a SNP in the CYP2C19 gene and is linked to poor clopidogrel metabolic activation. rs4244285 is associated with reduced enzyme activity of CYP2C19 and lower concentration of clopidogrel active metabolite. likely responsive
drug response, no assertion criteria provided	literature only	OMIM	May 14, 2018	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

This 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 provided

literature only

OMIM

Jun 01, 2009

- -

Mephenytoin, poor metabolism of

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over