12-132620590-C-G

Variant names:

• chr12-132620590-C-G
• rs199743808
• NM_170682.4:c.774+7C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_170682.4(P2RX2):​c.774+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,527,748 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: P2RX2 NM_170682.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00300
• 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.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.782465).
• BP6: Variant 12-132620590-C-G is Benign according to our data. Variant chr12-132620590-C-G is described in ClinVar as Benign. ClinVar VariationId is 226988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 257 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX2	NM_170682.4	c.774+7C>G		splice_region_variant, intron_variant	Intron 7 of 10	ENST00000643471.2	NP_733782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX2	ENST00000643471.2	c.774+7C>G		splice_region_variant, intron_variant	Intron 7 of 10		NM_170682.4	ENSP00000494644.1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 151758 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000516 AC: 128 AN: 248018 AF XY: 0.000372

Gnomad AFR exome AF: 0.00693

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000207 AC: 285 AN: 1375870 Hom.: 1 Cov.: 43 AF XY: 0.000165 AC XY: 113 AN XY: 686928

African (AFR) AF: 0.00721 AC: 230 AN: 31888

American (AMR) AF: 0.000567 AC: 25 AN: 44114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 38272

South Asian (SAS) AF: 0.00 AC: 0 AN: 84786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.00000384 AC: 4 AN: 1042148

Other (OTH) AF: 0.000456 AC: 26 AN: 57034

GnomAD4 genome AF: 0.00169 AC: 257 AN: 151878 Hom.: 0 Cov.: 34 AF XY: 0.00155 AC XY: 115 AN XY: 74260

African (AFR) AF: 0.00602 AC: 250 AN: 41560

American (AMR) AF: 0.000327 AC: 5 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10384

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67900

Other (OTH) AF: 0.000951 AC: 2 AN: 2102

Alfa AF: 0.000752 Hom.: 0

Bravo AF: 0.00216

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

774+7C>G in intron 7 of P2RX2: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 0.6% (27/4404) of African American chromosomes fro m a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washin gton.edu/EVS; dbSNP rs199743808). -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The P2RX2 c.672+2C>G variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs199743808) and ClinVar (reported as benign by Invitae and Laboratory for Molecular Medicine). The variant was identified in control databases in 184 of 279412 chromosomes at a frequency of 0.0006585 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 166 of 24874 chromosomes (freq: 0.006674) and Latino in 18 of 35382 chromosomes (freq: 0.000509), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The c.672+2C>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. However, only three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. Further, on other P2RX2 transcripts this variant does not fall within the splicing consensus sequence. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

not provided Benign:2

Oct 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.4
DANN	Benign	0.68
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.00078	N
PhyloP100		-0.0030
GERP RS		-4.0
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199743808; hg19: chr12-133197176;