rs143664462

Variant names:

• chr12-132619476-G-A
• rs143664462
• NM_170682.4:c.211G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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]

P2RX2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 41

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 229124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 230 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170682.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	NM_170682.4	MANE Select	c.211G>A	p.Glu71Lys	missense	Exon 2 of 11	NP_733782.1
	P2RX2	NM_170683.4		c.211G>A	p.Glu71Lys	missense	Exon 2 of 10	NP_733783.1
	P2RX2	NM_016318.4		c.211G>A	p.Glu71Lys	missense	Exon 2 of 10	NP_057402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	ENST00000643471.2	MANE Select	c.211G>A	p.Glu71Lys	missense	Exon 2 of 11	ENSP00000494644.1
	P2RX2	ENST00000343948.8	TSL:1	c.211G>A	p.Glu71Lys	missense	Exon 2 of 10	ENSP00000343339.4
	P2RX2	ENST00000350048.9	TSL:1	c.211G>A	p.Glu71Lys	missense	Exon 2 of 10	ENSP00000343904.5

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

GnomAD2 exomes AF: 0.00156 AC: 390 AN: 249322 AF XY: 0.00155

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 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

African (AFR) AF: 0.000359 AC: 12 AN: 33450

American (AMR) AF: 0.00168 AC: 75 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.000758 AC: 40 AN: 52768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00339 AC: 3766 AN: 1111482

Other (OTH) AF: 0.00270 AC: 163 AN: 60330

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

African (AFR) AF: 0.000602 AC: 25 AN: 41520

American (AMR) AF: 0.000850 AC: 13 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00263 AC: 179 AN: 67960

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00235 Hom.: 1

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

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

P2RX2: BS1, BS2

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.63
MPC		2.0
ClinPred		0.070	T
GERP RS		4.4
Varity_R		0.71
gMVP		0.84
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs143664462; hg19: chr12-133196062; COSMIC: COSV100268803; COSMIC: COSV100268803;