Genetic Variant P2RX2:p.Arg437Leu (chr12-132621866-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_170682.4(P2RX2):c.1310G>T(p.Arg437Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. R437Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

P2RX2
NM_170682.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.992

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

P2RX2 links:

ENSG00000280311 (HGNC:):

ENSG00000280311 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06442988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX2	NM_170682.4 link	c.1310G>T	p.Arg437Leu	missense_variant	Exon 11 of 11	ENST00000643471.2	NP_733782.1	Q9UBL9-1Q32MC3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX2	ENST00000643471.2 link	c.1310G>T	p.Arg437Leu	missense_variant	Exon 11 of 11		NM_170682.4	ENSP00000494644.1		Q9UBL9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460972

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726838

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111828

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.27

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.17

T;T;.;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.63

.;T;T;T;T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.064

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;N;.;.;.;.

PhyloP100

-0.99

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

.;N;N;N;N;N

REVEL

Benign

0.045

Sift

Uncertain

0.0030

.;D;D;D;D;D

Sift4G

Benign

0.33

.;T;T;T;T;T

Polyphen

0.051

B;B;B;B;B;B

Vest4

0.078, 0.25, 0.16, 0.15, 0.18

MutPred

0.17

Gain of glycosylation at P434 (P = 0.1239);Gain of glycosylation at P434 (P = 0.1239);.;.;.;.;

MVP

0.15

MPC

0.12

ClinPred

0.30

GERP RS

-4.0

Varity_R

0.074

gMVP

0.18

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over