12-132619443-G-T

Variant names:

• chr12-132619443-G-T
• rs587777692
• NM_170682.4:c.178G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM2 PP3 PP5

The NM_170682.4(P2RX2):​c.178G>T​(p.Val60Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V60I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.84
• Publications: 18 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_170682.4 (P2RX2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761
• PP5: Variant 12-132619443-G-T is Pathogenic according to our data. Variant chr12-132619443-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 155762.Status of the report is no_assertion_criteria_provided, 0 stars.

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.178G>T	p.Val60Leu	missense	Exon 2 of 11	NP_733782.1
	P2RX2	NM_170683.4		c.178G>T	p.Val60Leu	missense	Exon 2 of 10	NP_733783.1
	P2RX2	NM_016318.4		c.178G>T	p.Val60Leu	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.178G>T	p.Val60Leu	missense	Exon 2 of 11	ENSP00000494644.1
	P2RX2	ENST00000343948.8	TSL:1	c.178G>T	p.Val60Leu	missense	Exon 2 of 10	ENSP00000343339.4
	P2RX2	ENST00000350048.9	TSL:1	c.178G>T	p.Val60Leu	missense	Exon 2 of 10	ENSP00000343904.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 41 Pathogenic:1

Feb 05, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-1.1	T
PhyloP100		8.8
PROVEAN	Benign	0.14	N
REVEL	Benign	0.23
Sift	Benign	0.15	T
Sift4G	Benign	0.066	T
Polyphen		0.63	P
Vest4		0.51
MutPred		0.71		Loss of MoRF binding (P = 0.0155)
MVP		0.60
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.67
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777692; hg19: chr12-133196029;