rs587777692

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-132619443-G-A
• chr12-132619443-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_170682.4(P2RX2):​c.178G>A​(p.Val60Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,876 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V60L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.84
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

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.178G>A	p.Val60Ile	missense	Exon 2 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_170683.4		c.178G>A	p.Val60Ile	missense	Exon 2 of 10	NP_733783.1	Q9UBL9-4
	P2RX2	NM_016318.4		c.178G>A	p.Val60Ile	missense	Exon 2 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.178G>A	p.Val60Ile	missense	Exon 2 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000343948.8	TSL:1	c.178G>A	p.Val60Ile	missense	Exon 2 of 10	ENSP00000343339.4	Q9UBL9-4
	P2RX2	ENST00000350048.9	TSL:1	c.178G>A	p.Val60Ile	missense	Exon 2 of 10	ENSP00000343904.5	Q9UBL9-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726308

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52438

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111328

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 32

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
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
PhyloP100		8.8
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Benign	0.13	T
Sift4G	Uncertain	0.053	T
Polyphen		0.99	D
Vest4		0.43
MutPred		0.70		Loss of MoRF binding (P = 0.0144)
MVP		0.71
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.49
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs587777692; hg19: chr12-133196029;