rs4244285

Positions:

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

Variant summary

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

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
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:1 O:4
• Conservation: PhyloP100: -0.801

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]

ACMG classification

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	UniProt
CYP2C19	NM_000769.4	c.681G>A	p.Pro227=	synonymous_variant	5/9	ENST00000371321.9

Ensembl

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

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

GnomAD3 exomes AF: 0.176 AC: 28518 AN: 161670 Hom.: 2972 AF XY: 0.181 AC XY: 16382 AN XY: 90276

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

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

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:1 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Other:1

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).

Mephenytoin, poor metabolism of Other:1

drug response, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Clopidogrel response Other:1

drug response, no assertion criteria provided

literature only

OMIM

May 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

Other links and lift over

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