rs4244285

Variant names:

• chr10-94781859-G-A
• rs4244285
• NM_000769.4:c.681G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-94781859-G-A
• chr10-94781859-G-C
• chr10-94781859-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_000769.4(CYP2C19):​c.681G>A​(p.Pro227Pro) 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
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:2 O:5
• Conservation: PhyloP100: -0.801
• Publications: 1021 publications found

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]

ENSG00000276490 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 10-94781859-G-A is Benign according to our data. Variant chr10-94781859-G-A is described in ClinVar as Likely_benign|other. ClinVar VariationId is 16897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.681G>A	p.Pro227Pro	synonymous_variant	Exon 5 of 9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9	c.681G>A	p.Pro227Pro	synonymous_variant	Exon 5 of 9	1	NM_000769.4	ENSP00000360372.3
ENSG00000276490	ENST00000464755.1	n.*439G>A		non_coding_transcript_exon_variant	Exon 10 of 14	2		ENSP00000483243.1
ENSG00000276490	ENST00000464755.1	n.*439G>A		3_prime_UTR_variant	Exon 10 of 14	2		ENSP00000483243.1
CYP2C19	ENST00000645461.1	n.1734G>A		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25424 AN: 151376 Hom.: 2358 Cov.: 32

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

GnomAD2 exomes AF: 0.176 AC: 28518 AN: 161670 AF XY: 0.181

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 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

African (AFR) AF: 0.180 AC: 4669 AN: 25872

American (AMR) AF: 0.104 AC: 2042 AN: 19654

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 2866 AN: 21636

East Asian (EAS) AF: 0.302 AC: 9559 AN: 31626

South Asian (SAS) AF: 0.319 AC: 19359 AN: 60616

European-Finnish (FIN) AF: 0.173 AC: 8799 AN: 50984

Middle Eastern (MID) AF: 0.110 AC: 586 AN: 5316

European-Non Finnish (NFE) AF: 0.146 AC: 152480 AN: 1043430

Other (OTH) AF: 0.164 AC: 8884 AN: 54018

GnomAD4 genome AF: 0.168 AC: 25442 AN: 151494 Hom.: 2363 Cov.: 32 AF XY: 0.172 AC XY: 12754 AN XY: 73968

African (AFR) AF: 0.177 AC: 7318 AN: 41316

American (AMR) AF: 0.130 AC: 1981 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 457 AN: 3462

East Asian (EAS) AF: 0.312 AC: 1608 AN: 5156

South Asian (SAS) AF: 0.332 AC: 1588 AN: 4780

European-Finnish (FIN) AF: 0.186 AC: 1934 AN: 10370

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.148 AC: 10042 AN: 67874

Other (OTH) AF: 0.153 AC: 323 AN: 2108

Alfa AF: 0.151 Hom.: 4719

Bravo AF: 0.160

Asia WGS AF: 0.302 AC: 1046 AN: 3474

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:2 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 07, 2018

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- 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

May 14, 2018

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Faculty of Pharmacy, Damascus University

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

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

not specified Benign:1

Mar 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 01, 2009

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mephenytoin, poor metabolism of Other:1

Jun 01, 2009

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	16
DANN	Benign	0.39
PhyloP100		-0.80
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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