rs1555299245

Variant names:

• chr12-132621259-G-A
• rs1555299245
• NM_170682.4:c.910G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_170682.4(P2RX2):​c.910G>A​(p.Ala304Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,750 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• 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: 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_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX2	NM_170682.4	c.910G>A	p.Ala304Thr	missense_variant	Exon 9 of 11	ENST00000643471.2	NP_733782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX2	ENST00000643471.2	c.910G>A	p.Ala304Thr	missense_variant	Exon 9 of 11		NM_170682.4	ENSP00000494644.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461750 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala304Thr variant in P2RX2 has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analysis suggest that the p.Ala304Thr variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, the clinical significance of the p.Ala304Thr variant is uncert ain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;T;.;.;.;.;.;.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M;M;.;M;.;.;.;M;.
PhyloP100		9.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	.;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0090	.;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.042	.;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D
Vest4		0.89, 0.56, 0.84, 0.82, 0.88, 0.93, 0.90, 0.83
MutPred		0.83		Gain of phosphorylation at A304 (P = 0.0349);Gain of phosphorylation at A304 (P = 0.0349);.;Gain of phosphorylation at A304 (P = 0.0349);.;.;.;Gain of phosphorylation at A304 (P = 0.0349);Gain of phosphorylation at A304 (P = 0.0349);
MVP		0.45
MPC		0.48
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.66
gMVP		0.90
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555299245; hg19: chr12-133197845;