rs1555299075

Variant names:

• chr12-132621026-A-G
• rs1555299075
• NM_170682.4:c.800A>G

Variant summary

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

The NM_170682.4(P2RX2):​c.800A>G​(p.Asn267Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• 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: 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=0.41136783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX2	NM_170682.4	c.800A>G	p.Asn267Ser	missense_variant	Exon 8 of 11	ENST00000643471.2	NP_733782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX2	ENST00000643471.2	c.800A>G	p.Asn267Ser	missense_variant	Exon 8 of 11		NM_170682.4	ENSP00000494644.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn267Ser variant in P2RX2 has not been previously reported in individuals with hearing loss and is absent from large population studies. Computational pr ediction tools and conservation analysis do not provide strong support for or ag ainst an impact to the protein. In summary, the clinical significance of the p.A sn267Ser variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.;.;.;.;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	.;T;D;T;D;D;D;T;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;.;M;.;.;.;M;.
PhyloP100		2.0
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	.;N;N;N;N;D;N;N;.
REVEL	Benign	0.084
Sift	Benign	0.082	.;T;D;T;T;T;T;T;.
Sift4G	Benign	0.25	.;T;T;T;T;T;T;T;T
Polyphen		0.84	P;P;P;P;P;P;P;P;P
Vest4		0.71, 0.48, 0.73, 0.63, 0.68, 0.68, 0.46, 0.38
MutPred		0.42		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.30
MPC		0.28
ClinPred		0.92	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.71
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555299075; hg19: chr12-133197612;