rs876657423

Variant names:

• chr12-132621877-ATCTCTGCCCCT-A
• rs876657423
• NM_170682.4:c.1325_1335delCTGCCCCTTCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_170682.4(P2RX2):​c.1325_1335delCTGCCCCTTCT​(p.Ser442fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,480 control chromosomes in the GnomAD database, including 29 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (15 hom.)
• Consequence: P2RX2 NM_170682.4 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.17
• Publications: 1 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

ENSG00000280311 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-132621877-ATCTCTGCCCCT-A is Benign according to our data. Variant chr12-132621877-ATCTCTGCCCCT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00892 (1358/152250) while in subpopulation AFR AF = 0.0312 (1297/41542). AF 95% confidence interval is 0.0298. There are 14 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1358 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.1325_1335delCTGCCCCTTCT	p.Ser442fs	frameshift	Exon 11 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_170683.4		c.1403_1413delCTGCCCCTTCT	p.Ser468fs	frameshift	Exon 10 of 10	NP_733783.1	Q9UBL9-4
	P2RX2	NM_016318.4		c.1253_1263delCTGCCCCTTCT	p.Ser418fs	frameshift	Exon 10 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.1325_1335delCTGCCCCTTCT	p.Ser442fs	frameshift	Exon 11 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000343948.8	TSL:1	c.1403_1413delCTGCCCCTTCT	p.Ser468fs	frameshift	Exon 10 of 10	ENSP00000343339.4	Q9UBL9-4
	P2RX2	ENST00000350048.9	TSL:1	c.1253_1263delCTGCCCCTTCT	p.Ser418fs	frameshift	Exon 10 of 10	ENSP00000343904.5	Q9UBL9-3

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 1358 AN: 152132 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00236 AC: 591 AN: 250266 AF XY: 0.00169

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000847 AC: 1237 AN: 1461230 Hom.: 15 AF XY: 0.000741 AC XY: 539 AN XY: 726950

African (AFR) AF: 0.0304 AC: 1018 AN: 33472

American (AMR) AF: 0.00190 AC: 85 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52924

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111924

Other (OTH) AF: 0.00172 AC: 104 AN: 60380

GnomAD4 genome AF: 0.00892 AC: 1358 AN: 152250 Hom.: 14 Cov.: 33 AF XY: 0.00863 AC XY: 643 AN XY: 74466

African (AFR) AF: 0.0312 AC: 1297 AN: 41542

American (AMR) AF: 0.00281 AC: 43 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68006

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00480 Hom.: 0

Bravo AF: 0.00965

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 41 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
La Branchor		0.61
BranchPoint Hunter		3.0
Mutation Taster		=191/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs876657423; hg19: chr12-133198463;