12-132618863-G-T

Variant names:

• chr12-132618863-G-T
• rs762889627
• NM_170682.4:c.47G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170682.4(P2RX2):​c.47G>T​(p.Arg16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000328 in 1,221,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0210

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2487953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX2	NM_170682.4	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 11	ENST00000643471.2	NP_733782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX2	ENST00000643471.2	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 11		NM_170682.4	ENSP00000494644.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000843 AC: 1 AN: 118630 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000865

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000328 AC: 4 AN: 1221194 Hom.: 0 Cov.: 31 AF XY: 0.00000333 AC XY: 2 AN XY: 599748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000516

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000643

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ExAC AF: 0.00000847 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with P2RX2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 16 of the P2RX2 protein (p.Arg16Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.;.;.;.;.;.;T
Eigen	Benign	-0.037
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.84	.;T;D;T;T;D;T;T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M;M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.4	.;N;N;N;D;N;N;N;.
REVEL	Benign	0.039
Sift	Uncertain	0.013	.;D;D;D;D;D;D;D;.
Sift4G	Benign	0.084	.;T;T;T;D;T;D;T;T
Polyphen		0.83	P;P;D;D;P;D;P;P;P
Vest4		0.25, 0.32, 0.28, 0.20, 0.23, 0.24, 0.21, 0.28
MutPred		0.49		Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);
MVP		0.54
MPC		1.9
ClinPred		0.78	D
GERP RS		3.0
Varity_R		0.20
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs762889627; hg19: chr12-133195449;