rs143664462

Positions:

• chr12-132619476-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_170682.4(P2RX2):​c.211G>A​(p.Glu71Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,612,632 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (12 hom.)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.18

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 Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Dann, FATHMM_MKL, M_CAP, PrimateAI [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.028756559).
• BP6: Variant 12-132619476-G-A is Benign according to our data. Variant chr12-132619476-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 229124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132619476-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 230 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P2RX2	NM_170682.4	c.211G>A	p.Glu71Lys	missense_variant	2/11	ENST00000643471.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P2RX2	ENST00000643471.2	c.211G>A	p.Glu71Lys	missense_variant	2/11		NM_170682.4	A2

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00156 AC: 390 AN: 249322 Hom.: 0 AF XY: 0.00155 AC XY: 209 AN XY: 135248

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00278 AC: 4057 AN: 1460498 Hom.: 12 Cov.: 33 AF XY: 0.00263 AC XY: 1914 AN XY: 726634

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000758

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74376

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00263

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00233 Hom.: 0

Bravo AF: 0.00148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00149 AC: 181

Asia WGS AF: 0.000289 AC: 1 AN: 3474

EpiCase AF: 0.00327

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	P2RX2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2017

p.Glu71Lys in exon 2 of P2RX2: This variant is not expected to have clinical sig nificance because it has been identified in 0.3% (334/125162) of European chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs143664462). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T;.;.;.;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.029	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.59, 0.25, 0.52, 0.56, 0.53
MVP		0.63
MPC		2.0
ClinPred		0.070	T
GERP RS		4.4
Varity_R		0.71
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143664462; hg19: chr12-133196062; COSMIC: COSV100268803; COSMIC: COSV100268803;