chr12-132618856-G-C

Variant names:

• chr12-132618856-G-C
• rs1286367250
• NM_170682.4:c.40G>C

Variant summary

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

The NM_170682.4(P2RX2):​c.40G>C​(p.Ala14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000823 in 1,214,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

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 rank	MANE	Protein	UniProt
P2RX2	NM_170682.4	c.40G>C	p.Ala14Pro	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.40G>C	p.Ala14Pro	missense_variant	Exon 1 of 11		NM_170682.4	ENSP00000494644.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.23e-7 AC: 1 AN: 1214590 Hom.: 0 Cov.: 31 AF XY: 0.00000168 AC XY: 1 AN XY: 595982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000530

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

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.;.;.;.;.;.;T
Eigen	Benign	0.017
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.75	.;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.42	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.99	.;N;N;N;N;N;N;N;.
REVEL	Benign	0.17
Sift	Uncertain	0.017	.;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.041	.;D;D;D;D;D;D;T;D
Polyphen		0.99	D;D;D;D;D;D;D;D;D
Vest4		0.43, 0.35, 0.43, 0.32, 0.39, 0.32, 0.38, 0.52
MutPred		0.62		Gain of glycosylation at A14 (P = 0.0126);Gain of glycosylation at A14 (P = 0.0126);Gain of glycosylation at A14 (P = 0.0126);Gain of glycosylation at A14 (P = 0.0126);Gain of glycosylation at A14 (P = 0.0126);Gain of glycosylation at A14 (P = 0.0126);Gain of glycosylation at A14 (P = 0.0126);Gain of glycosylation at A14 (P = 0.0126);Gain of glycosylation at A14 (P = 0.0126);
MVP		0.52
MPC		2.1
ClinPred		0.73	D
GERP RS		3.9
Varity_R		0.56
gMVP		0.54

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: rs1286367250; hg19: chr12-133195442;