12-132621535-G-C

Variant names:

• chr12-132621535-G-C
• rs202138002
• NM_170682.4:c.1057G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_170682.4(P2RX2):​c.1057G>C​(p.Gly353Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.80

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 12-132621535-G-C is Pathogenic according to our data. Variant chr12-132621535-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 155763.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-132621535-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX2	NM_170682.4	c.1057G>C	p.Gly353Arg	missense_variant	Exon 10 of 11	ENST00000643471.2	NP_733782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX2	ENST00000643471.2	c.1057G>C	p.Gly353Arg	missense_variant	Exon 10 of 11		NM_170682.4	ENSP00000494644.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 41 Pathogenic:1

Jan 25, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Feb 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 353 of the P2RX2 protein (p.Gly353Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 24211385). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 155763). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt P2RX2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects P2RX2 function (PMID: 31636190). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;.;.;.;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;T;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M;M;.;M;.;.;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.4	.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.93, 0.76, 0.97, 0.91, 0.93, 0.94, 0.94
MutPred		0.96		Gain of methylation at G353 (P = 0.0357);Gain of methylation at G353 (P = 0.0357);.;Gain of methylation at G353 (P = 0.0357);.;.;.;Gain of methylation at G353 (P = 0.0357);
MVP		0.67
MPC		0.55
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs202138002; hg19: chr12-133198121;