P2RX2

protein-coding

purinergic receptor P2X 2, the group of Purinergic receptors P2X

Gene summary

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]

Previous symbols:

DFNA41

MANE transcript

NM_170682.4

Inheritance

ClinVar variants

P:5U:181B:85

Top phenotype

Deafness, autosomal dominant 41

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr12:132,618,776-132,622,388

External References & Databases

Ensembl (ENSG00000187848)

Transcript & Mutation Effects

hg38 • Region Span ~3.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing loss 41STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011994

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 41STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011994

Submitter: PanelApp Australia

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

P2RX2 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2013 (Yan et al. 2013, PMID: 23345450). Three missense variants that have been reported in four probands in four publications are included in this curation (PMIDs: 23345450, 24211385, 29986705, 34425661). The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family. An additional family was reported in which hearing loss co occurred with a mitochondrial disorder, however there wasn't strong evidence in support of pathogenicity of the P2RX2 variant for this phenotype and the variant was present in gnomAD (25788561). Functional evidence suggests a dominant negative mechanism (23345450). Substantial experimental evidence suggests that the P2RX2 receptor modulates a temporary threshold shift that protects the cochlea from overstimulation by loud noise exposure (23592720). This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 23345450, 33791800, 23592720, 18491132). Loss of the P2RX2 receptor in mice increases susceptibility to noise-induced hearing loss, and a significant correlation was found in a large Chinese family between noise exposure during adolescence and severity of hearing loss (PMIDs: 23345450, 33791800). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 02/20/2018. It was reevaluated on 09/21/2022. Although a new case with hearing loss (29986705) and a new knock-in mouse model with progressive hearing loss (33791800) were scored, the classification did not change (SOP Version 9).

autosomal dominant nonsyndromic hearing loss 41LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011994

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 41AD

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 12161595; 23345450; 24211385

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to P2RX2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 237

not specifiedTotal: 143

P2RX2-related disorderTotal: 58

Autosomal dominant nonsyndromic hearing loss 41Total: 15

Bilateral sensorineural hearing impairmentTotal: 1

Autosomal dominant nonsyndromic hearing lossTotal: 1

P2RX2-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_170682.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	48 clinvar	4 clinvar	60
missense	3 clinvar	1 clinvar	145 clinvar	31 clinvar		180
nonsense			6 clinvar	1 clinvar		7
start loss			1 clinvar			1
frameshift		1 clinvar	9 clinvar	1 clinvar		11
splice donor/acceptor (+/-2bp)			12 clinvar			12
Total	3	2	181	81	4	271

Highest pathogenic variant AF is 0.000010168673

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_170682.4	RefSeq	NP_733782.1	11	MANE Select
ENST00000643471.2	Ensembl	ENSP00000494644.1	11	MANE Select
NM_001282164.2	RefSeq	NP_001269093.1	11	Standard
NM_001282165.2	RefSeq	NP_001269094.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Calcium signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Taste transduction - Homo sapiens (human)
Hemostasis
Elevation of cytosolic Ca2+ levels

Biological Process

response to hypoxia
response to ischemia
detection of hypoxic conditions in blood by carotid body chemoreceptor signaling
cation transport
neuromuscular synaptic transmission

Molecular Function

purinergic nucleotide receptor activity
extracellularly ATP-gated cation channel activity
ATP binding
ligand-gated ion channel activity
ATP-gated ion channel activity

Cellular Component

integral component of nuclear inner membrane
plasma membrane
integral component of plasma membrane
integral component of membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000343948
Coding exons: 10
Length: 3607
Individuals with no LoFs: 125452
Homozygous LoFs: 1
Heterozygous LoFs: 292
Defined: 125745
p: 0.00117

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.232	285	296	0.962	0.0000171	3204
Missense (PolyPhen)		102	111.21	0.91721		1305
Synonymous	-0.610	137	128	1.07	0.00000824	1003
Loss of Function	0.180	19	19.9	0.957	8.47e-7	232

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00018	rare
Latino/Admixed American	0.00045	0.00043	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.0073	0.0069	notable
European (Non-Finnish)	0.00094	0.00090	rare
South Asian	0.00047	0.00046	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ion channel gated by extracellular ATP involved in a variety of cellular responses, such as excitatory postsynaptic responses in sensory neurons, neuromuscular junctions (NMJ) formation, hearing, perception of taste and peristalsis. In the inner ear, regulates sound transduction and auditory neurotransmission, outer hair cell electromotility, inner ear gap junctions, and K(+) recycling. Mediates synaptic transmission between neurons and from neurons to smooth muscle. {ECO:0000269|PubMed:23345450}.;
Disease: DISEASE: Deafness, autosomal dominant, 41 (DFNA41) [MIM:608224]: A form of non-syndromic deafness characterized by onset of progressive sensorineural hearing loss usually in the second decade. The hearing loss is severe and ultimately affects all frequencies. Exposure to noise exacerbates the hearing loss, particularly at high frequencies. {ECO:0000269|PubMed:23345450, ECO:0000269|PubMed:24211385}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.162

Intolerance Scores

LoFtool: 0.988
RVIS EVS: -0.62
RVIS percentile EVS: 17.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.117

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium