12-132618901-G-T

Variant names:

• chr12-132618901-G-T
• rs756505870
• NM_170682.4:c.85G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_170682.4(P2RX2):​c.85G>T​(p.Glu29*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,362,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: P2RX2 NM_170682.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27
• 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 0 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	NM_170682.4	MANE Select	c.85G>T	p.Glu29*	stop_gained	Exon 1 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_170683.4		c.85G>T	p.Glu29*	stop_gained	Exon 1 of 10	NP_733783.1	Q9UBL9-4
	P2RX2	NM_016318.4		c.85G>T	p.Glu29*	stop_gained	Exon 1 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.85G>T	p.Glu29*	stop_gained	Exon 1 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000343948.8	TSL:1	c.85G>T	p.Glu29*	stop_gained	Exon 1 of 10	ENSP00000343339.4	Q9UBL9-4
	P2RX2	ENST00000350048.9	TSL:1	c.85G>T	p.Glu29*	stop_gained	Exon 1 of 10	ENSP00000343904.5	Q9UBL9-3

Frequencies

GnomAD3 genomes AF: 0.0000601 AC: 9 AN: 149852 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000594

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 119796 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 5 AN: 1212368 Hom.: 0 Cov.: 31 AF XY: 0.00000168 AC XY: 1 AN XY: 593760

African (AFR) AF: 0.00 AC: 0 AN: 24816

American (AMR) AF: 0.0000544 AC: 1 AN: 18398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15882

East Asian (EAS) AF: 0.00 AC: 0 AN: 30360

South Asian (SAS) AF: 0.00 AC: 0 AN: 44744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 983390

Other (OTH) AF: 0.0000840 AC: 4 AN: 47592

GnomAD4 genome AF: 0.0000601 AC: 9 AN: 149852 Hom.: 0 Cov.: 29 AF XY: 0.0000684 AC XY: 5 AN XY: 73110

African (AFR) AF: 0.00 AC: 0 AN: 41106

American (AMR) AF: 0.000594 AC: 9 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67190

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000196

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		3.3
Vest4		0.67
GERP RS		4.1
PromoterAI		-0.044	Neutral
Mutation Taster		=3/197	disease causing (fs/PTC)

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: rs756505870; hg19: chr12-133195487;