chr12-132621493-A-T

Variant names:

• chr12-132621493-A-T
• rs1555299483
• NM_170682.4:c.1015A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_170682.4(P2RX2):​c.1015A>T​(p.Ile339Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• Publications: 0 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27525157).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	NM_170682.4	MANE Select	c.1015A>T	p.Ile339Phe	missense	Exon 10 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_170683.4		c.1015A>T	p.Ile339Phe	missense	Exon 10 of 10	NP_733783.1	Q9UBL9-4
	P2RX2	NM_016318.4		c.943A>T	p.Ile315Phe	missense	Exon 9 of 10	NP_057402.1	Q9UBL9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	ENST00000643471.2	MANE Select	c.1015A>T	p.Ile339Phe	missense	Exon 10 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000343948.8	TSL:1	c.1015A>T	p.Ile339Phe	missense	Exon 10 of 10	ENSP00000343339.4	Q9UBL9-4
	P2RX2	ENST00000350048.9	TSL:1	c.943A>T	p.Ile315Phe	missense	Exon 9 of 10	ENSP00000343904.5	Q9UBL9-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.28	T
PhyloP100		3.0
Polyphen		0.47	P
Vest4		0.35
MVP		0.61
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.78
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs1555299483; hg19: chr12-133198079;