chr12-132619752-T-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_ModerateBP6BS2

The NM_170682.4(P2RX2):​c.381+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,609,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

P2RX2
NM_170682.4 splice_donor, intron

Scores

1
3
3
Splicing: ADA: 0.9996
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.25

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.050847456 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
BP6
Variant 12-132619752-T-C is Benign according to our data. Variant chr12-132619752-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504852.
BS2
High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
P2RX2NM_170682.4 linkc.381+2T>C splice_donor_variant, intron_variant Intron 3 of 10 ENST00000643471.2 NP_733782.1 Q9UBL9-1Q32MC3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
P2RX2ENST00000643471.2 linkc.381+2T>C splice_donor_variant, intron_variant Intron 3 of 10 NM_170682.4 ENSP00000494644.1 Q9UBL9-1

Frequencies

GnomAD3 genomes
AF:
0.000224
AC:
34
AN:
152034
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.000427
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000118
AC:
28
AN:
238126
AF XY:
0.000107
show subpopulations
Gnomad AFR exome
AF:
0.0000708
Gnomad AMR exome
AF:
0.0000591
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000226
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000300
AC:
437
AN:
1457584
Hom.:
0
Cov.:
33
AF XY:
0.000275
AC XY:
199
AN XY:
724876
show subpopulations
African (AFR)
AF:
0.0000599
AC:
2
AN:
33394
American (AMR)
AF:
0.0000676
AC:
3
AN:
44376
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25942
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39644
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86036
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51852
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5754
European-Non Finnish (NFE)
AF:
0.000370
AC:
411
AN:
1110392
Other (OTH)
AF:
0.000299
AC:
18
AN:
60194
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
22
44
67
89
111
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000223
AC:
34
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74396
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41524
American (AMR)
AF:
0.000196
AC:
3
AN:
15306
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5144
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.000427
AC:
29
AN:
67960
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.537
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000333
Hom.:
0
Bravo
AF:
0.000174
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000234
AC:
2
ExAC
AF:
0.000166
AC:
20
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Apr 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 01, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1
Dec 04, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.381+2T>C variant in P2RX2 has not been previously reported in individuals with hearing loss. It has been identified in 32/119906 European chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200978001). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predi cted to cause altered splicing leading to an abnormal or absent protein. However , to date only 3 missense variants in P2RX2 have been associated with hearing lo ss (Yan 2013, Faletra 2014, Moteki 2015), and it is not clear if loss-of-functio n variant in P2RX2 can result in hearing loss. In summary, the clinical signific ance of the c.381+2T>C variant is uncertain due to lack of data supporting loss- of-function of P2RX2 as a disease mechanism. -

Autosomal dominant nonsyndromic hearing loss 41 Uncertain:1
Feb 22, 2019
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
26
DANN
Uncertain
0.98
Eigen
Pathogenic
0.80
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.95
D
PhyloP100
3.3
GERP RS
4.0
Mutation Taster
=1/99
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.79
SpliceAI score (max)
0.83
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.83
Position offset: -2

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

Publications

Other links and lift over

dbSNP: rs200978001; hg19: chr12-133196338; API