Genetic Variant P2RX2:p.Ala12Glu (chr12-132618851-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_170682.4(P2RX2):c.35C>A(p.Ala12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,210,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A12V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

P2RX2
NM_170682.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.04

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: 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09030199).

BS2

High AC in GnomAdExome4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
P2RX2	NM_170682.4	MANE Select	c.35C>A	p.Ala12Glu	missense	Exon 1 of 11	NP_733782.1	Q9UBL9-1
P2RX2	NM_170683.4		c.35C>A	p.Ala12Glu	missense	Exon 1 of 10	NP_733783.1	Q9UBL9-4
P2RX2	NM_016318.4		c.35C>A	p.Ala12Glu	missense	Exon 1 of 10	NP_057402.1	Q9UBL9-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
P2RX2	ENST00000643471.2	MANE Select	c.35C>A	p.Ala12Glu	missense	Exon 1 of 11	ENSP00000494644.1	Q9UBL9-1
P2RX2	ENST00000343948.8	TSL:1	c.35C>A	p.Ala12Glu	missense	Exon 1 of 10	ENSP00000343339.4	Q9UBL9-4
P2RX2	ENST00000350048.9	TSL:1	c.35C>A	p.Ala12Glu	missense	Exon 1 of 10	ENSP00000343904.5	Q9UBL9-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000956

AC:

AN:

104632

AF XY:

0.0000167

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000195

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000496

AC:

AN:

1210046

Hom.:

Cov.:

AF XY:

0.00000843

AC XY:

AN XY:

592942

show subpopulations

African (AFR)

AF:

0.0000403

AC:

AN:

24832

American (AMR)

AF:

0.00

AC:

AN:

18186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15934

East Asian (EAS)

AF:

0.00

AC:

AN:

29952

South Asian (SAS)

AF:

0.0000225

AC:

AN:

44450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41712

Middle Eastern (MID)

AF:

0.000897

AC:

AN:

4458

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

983186

Other (OTH)

AF:

0.00

AC:

AN:

47336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000258

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

5.8

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.095

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.090

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.0

PhyloP100

-1.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.46

REVEL

Benign

0.027

Sift

Benign

0.057

Sift4G

Benign

0.066

Polyphen

0.084

Vest4

0.21

MutPred

0.35

Gain of ubiquitination at K7 (P = 0.0355)

MVP

0.32

MPC

1.0

ClinPred

0.051

GERP RS

0.34

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.11

gMVP

0.33

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over