rs876657424

Variant names:

• chr12-132620989-CCTT-C
• rs876657424
• NM_170682.4:c.775-8_775-6delCTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_170682.4(P2RX2):​c.775-8_775-6delCTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,613,276 control chromosomes in the GnomAD database, including 183 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (96 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (87 hom.)
• Consequence: P2RX2 NM_170682.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.314
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-132620989-CCTT-C is Benign according to our data. Variant chr12-132620989-CCTT-C is described in ClinVar as Benign. ClinVar VariationId is 226989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	NM_170682.4	MANE Select	c.775-8_775-6delCTT		splice_region intron	N/A	NP_733782.1
	P2RX2	NM_170683.4		c.775-8_775-6delCTT		splice_region intron	N/A	NP_733783.1
	P2RX2	NM_016318.4		c.703-8_703-6delCTT		splice_region intron	N/A	NP_057402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	ENST00000643471.2	MANE Select	c.775-11_775-9delCTT		intron	N/A	ENSP00000494644.1
	P2RX2	ENST00000343948.8	TSL:1	c.775-11_775-9delCTT		intron	N/A	ENSP00000343339.4
	P2RX2	ENST00000350048.9	TSL:1	c.703-11_703-9delCTT		intron	N/A	ENSP00000343904.5

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2637 AN: 151414 Hom.: 96 Cov.: 31

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00598

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000839

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00915

GnomAD2 exomes AF: 0.00443 AC: 1112 AN: 251286 AF XY: 0.00330

Gnomad AFR exome AF: 0.0598

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00187 AC: 2739 AN: 1461744 Hom.: 87 AF XY: 0.00163 AC XY: 1186 AN XY: 727198

African (AFR) AF: 0.0652 AC: 2182 AN: 33468

American (AMR) AF: 0.00378 AC: 169 AN: 44718

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

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

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1111958

Other (OTH) AF: 0.00414 AC: 250 AN: 60384

GnomAD4 genome AF: 0.0175 AC: 2653 AN: 151532 Hom.: 96 Cov.: 31 AF XY: 0.0171 AC XY: 1267 AN XY: 74012

African (AFR) AF: 0.0614 AC: 2531 AN: 41248

American (AMR) AF: 0.00597 AC: 91 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.000420 AC: 2 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67880

Other (OTH) AF: 0.00906 AC: 19 AN: 2098

Alfa AF: 0.00961 Hom.: 4

Bravo AF: 0.0199

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	P2RX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31
Mutation Taster		=99/1	polymorphism (auto)

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: rs876657424; hg19: chr12-133197575;