ENST00000352418.8:c.118C>A

Variant names:

• chr12-132619451-C-A
• rs75585377
• ENST00000352418.8:c.118C>A
• P2RX2 p.Arg40Ser

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The ENST00000352418.8(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 0.000000685 in 1,460,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: P2RX2 ENST00000352418.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000352418.8
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000352418.8. 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.186C>A	p.Ile62Ile	synonymous	Exon 2 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_012226.5		c.118C>A	p.Arg40Ser	missense	Exon 2 of 9	NP_036358.2
	P2RX2	NM_170683.4		c.186C>A	p.Ile62Ile	synonymous	Exon 2 of 10	NP_733783.1	Q9UBL9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	ENST00000352418.8	TSL:1	c.118C>A	p.Arg40Ser	missense	Exon 2 of 9	ENSP00000341419.4	Q9UBL9-6
	P2RX2	ENST00000643471.2	MANE Select	c.186C>A	p.Ile62Ile	synonymous	Exon 2 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000343948.8	TSL:1	c.186C>A	p.Ile62Ile	synonymous	Exon 2 of 10	ENSP00000343339.4	Q9UBL9-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460132 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726444

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52534

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111428

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.32	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.18
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.060
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.015	D
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs75585377;

hg19: chr12-133196037;