12-132618851-C-T

Variant names:

• chr12-132618851-C-T
• rs772335034
• NM_170682.4:c.35C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170682.4(P2RX2):​c.35C>T​(p.Ala12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,210,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.04
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09699121).

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.35C>T	p.Ala12Val	missense	Exon 1 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_170683.4		c.35C>T	p.Ala12Val	missense	Exon 1 of 10	NP_733783.1	Q9UBL9-4
	P2RX2	NM_016318.4		c.35C>T	p.Ala12Val	missense	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.35C>T	p.Ala12Val	missense	Exon 1 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000343948.8	TSL:1	c.35C>T	p.Ala12Val	missense	Exon 1 of 10	ENSP00000343339.4	Q9UBL9-4
	P2RX2	ENST00000350048.9	TSL:1	c.35C>T	p.Ala12Val	missense	Exon 1 of 10	ENSP00000343904.5	Q9UBL9-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000165 AC: 2 AN: 1210040 Hom.: 0 Cov.: 31 AF XY: 0.00000337 AC XY: 2 AN XY: 592938

⚠️ 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: 24832

American (AMR) AF: 0.00 AC: 0 AN: 18186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15934

East Asian (EAS) AF: 0.00 AC: 0 AN: 29952

South Asian (SAS) AF: 0.00 AC: 0 AN: 44448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4458

European-Non Finnish (NFE) AF: 0.00000203 AC: 2 AN: 983182

Other (OTH) AF: 0.00 AC: 0 AN: 47336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

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	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-1.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.027
Sift	Benign	0.068	T
Sift4G	Uncertain	0.022	D
Polyphen		0.0030	B
Vest4		0.10
MutPred		0.29		Loss of helix (P = 0.0237)
MVP		0.34
MPC		0.81
ClinPred		0.071	T
GERP RS		0.34
PromoterAI		-0.0080	Neutral
Varity_R		0.041
gMVP		0.18
Mutation Taster		=93/7	polymorphism

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: rs772335034; hg19: chr12-133195437;