12-132619451-C-T

Variant names:

• chr12-132619451-C-T
• rs75585377
• ENST00000352418.8:c.118C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_170682.4(P2RX2):​c.186C>T​(p.Ile62Ile) variant causes a synonymous 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 32)
  • Exomes 𝑓: 0.015 (147 hom.)
• Consequence: P2RX2 NM_170682.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.180
• Publications: 10 publications found

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]

P2RX2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 41

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 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 GnomAdExome4. There are 10965 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1574 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX2	NM_170682.4	c.186C>T	p.Ile62Ile	synonymous_variant	Exon 2 of 11	ENST00000643471.2	NP_733782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX2	ENST00000643471.2	c.186C>T	p.Ile62Ile	synonymous_variant	Exon 2 of 11		NM_170682.4	ENSP00000494644.1

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

GnomAD2 exomes AF: 0.0112 AC: 2778 AN: 248670 AF XY: 0.0120

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 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

African (AFR) AF: 0.00191 AC: 64 AN: 33426

American (AMR) AF: 0.00980 AC: 438 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 539 AN: 26070

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39656

South Asian (SAS) AF: 0.0163 AC: 1403 AN: 86248

European-Finnish (FIN) AF: 0.00761 AC: 400 AN: 52534

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5762

European-Non Finnish (NFE) AF: 0.0163 AC: 18062 AN: 1111402

Other (OTH) AF: 0.0132 AC: 795 AN: 60320

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

African (AFR) AF: 0.00335 AC: 139 AN: 41528

American (AMR) AF: 0.0124 AC: 190 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3466

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5132

South Asian (SAS) AF: 0.0131 AC: 63 AN: 4824

European-Finnish (FIN) AF: 0.00661 AC: 70 AN: 10592

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0149 AC: 1013 AN: 67944

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0134 Hom.: 39

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

P2RX2: BP4, BS1, BS2 -

Sep 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jan 02, 2018

GeneDx

Significance: 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. -

P2RX2-related disorder Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.18
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
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

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