rs75585377

chr12-132619451-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000352418.8(P2RX2):c.118C>T(p.Arg40Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,612,196 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 32)
  • Exomes 𝑓: 0.015 (147 hom.)
• Consequence: P2RX2 ENST00000352418.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.180

Genes affected

P2RX2 (HGNC:15459): (purinergic receptor P2X 2) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel. Binding to ATP mediates synaptic transmission between neurons and from neurons to smooth muscle. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-132619451-C-T is Benign according to our data. Variant chr12-132619451-C-T is described in ClinVar as [Benign]. Clinvar id is 226983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132619451-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0149 (21786/1460106) while in subpopulation SAS AF= 0.0163 (1403/86248). AF 95% confidence interval is 0.0161. There are 147 homozygotes in gnomad4_exome. There are 10965 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1574 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P2RX2	NM_170682.4	c.186C>T	p.Ile62=	synonymous_variant	2/11	ENST00000643471.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P2RX2	ENST00000643471.2	c.186C>T	p.Ile62=	synonymous_variant	2/11		NM_170682.4	A2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1574 AN: 151982 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00661

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0112 AC: 2778 AN: 248670 Hom.: 19 AF XY: 0.0120 AC XY: 1621 AN XY: 135026

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00898

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0144

Gnomad FIN exome AF: 0.00679

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0149 AC: 21786 AN: 1460106 Hom.: 147 Cov.: 33 AF XY: 0.0151 AC XY: 10965 AN XY: 726432

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00980

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.00761

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0103 AC: 1574 AN: 152090 Hom.: 9 Cov.: 32 AF XY: 0.00990 AC XY: 736 AN XY: 74336

Gnomad4 AFR AF: 0.00335

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.00661

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0137 Hom.: 18

Bravo AF: 0.0108

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0107 AC: 1302

Asia WGS AF: 0.00607 AC: 22 AN: 3472

EpiCase AF: 0.0181

EpiControl AF: 0.0158

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	P2RX2: BP4, BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ile62Ile in exon 2 of P2RX2: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1.5% (133/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs75585377). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 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. -

P2RX2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.73	D;D;D;D;D;D;D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.82	P
Vest4		0.27
ClinPred		0.037	T
GERP RS		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75585377; hg19: chr12-133196037; COSMIC: COSV57691870; COSMIC: COSV57691870;