12-132618880-T-C

Position:

• chr12-132618880-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_170682.4(P2RX2):​c.64T>C​(p.Trp22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.975

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RX2	NM_170682.4	c.64T>C	p.Trp22Arg	missense_variant	1/11	ENST00000643471.2	NP_733782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX2	ENST00000643471.2	c.64T>C	p.Trp22Arg	missense_variant	1/11		NM_170682.4	ENSP00000494644	A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1225560 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 601916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 04, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt P2RX2 protein function. This variant has not been reported in the literature in individuals affected with P2RX2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 22 of the P2RX2 protein (p.Trp22Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.58	D;D;.;.;.;.;.;.;T
Eigen	Benign	-0.0076
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.68	.;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M;M;M;.
MutationTaster	Benign	0.60	D;D;D;D;D;N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	.;D;D;D;D;D;D;D;.
REVEL	Benign	0.17
Sift	Benign	0.077	.;T;T;T;D;T;D;T;.
Sift4G	Benign	0.13	.;T;T;T;D;T;D;T;T
Polyphen		0.62	P;P;B;P;P;P;P;P;P
Vest4		0.67, 0.54, 0.69, 0.45, 0.68, 0.62, 0.65, 0.60
MutPred		0.51		Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);
MVP		0.45
MPC		1.8
ClinPred		0.35	T
GERP RS		4.1
Varity_R		0.48
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1382780227; hg19: chr12-133195466;