12-132618934-C-A

Variant names:

• chr12-132618934-C-A
• rs747266387
• NM_170682.4:c.118C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_170682.4(P2RX2):​c.118C>A​(p.Arg40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000085 in 1,176,460 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.127
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3081751).
• BP6: Variant 12-132618934-C-A is Benign according to our data. Variant chr12-132618934-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2551691.
• BS2: High AC in GnomAdExome4 at 10 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.118C>A	p.Arg40Ser	missense	Exon 1 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_170683.4		c.118C>A	p.Arg40Ser	missense	Exon 1 of 10	NP_733783.1	Q9UBL9-4
	P2RX2	NM_016318.4		c.118C>A	p.Arg40Ser	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.118C>A	p.Arg40Ser	missense	Exon 1 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000343948.8	TSL:1	c.118C>A	p.Arg40Ser	missense	Exon 1 of 10	ENSP00000343339.4	Q9UBL9-4
	P2RX2	ENST00000350048.9	TSL:1	c.118C>A	p.Arg40Ser	missense	Exon 1 of 10	ENSP00000343904.5	Q9UBL9-3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.0000260 AC: 3 AN: 115480 AF XY: 0.0000470

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: 0.0000501

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000850 AC: 10 AN: 1176460 Hom.: 0 Cov.: 31 AF XY: 0.0000105 AC XY: 6 AN XY: 570964

African (AFR) AF: 0.00 AC: 0 AN: 24434

American (AMR) AF: 0.00 AC: 0 AN: 17294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14628

East Asian (EAS) AF: 0.00 AC: 0 AN: 29872

South Asian (SAS) AF: 0.00 AC: 0 AN: 36752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4576

European-Non Finnish (NFE) AF: 0.00000831 AC: 8 AN: 962368

Other (OTH) AF: 0.0000435 AC: 2 AN: 45974

GnomAD4 genome Cov.: 28

ExAC AF: 0.0000252 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.13
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.090
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.12	T
Polyphen		0.78	P
Vest4		0.31
MutPred		0.56		Loss of MoRF binding (P = 0.0372)
MVP		0.51
MPC		1.4
ClinPred		0.37	T
GERP RS		3.1
PromoterAI		0.026	Neutral
Varity_R		0.39
gMVP		0.33
Mutation Taster		=83/17	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: rs747266387; hg19: chr12-133195520;