dbSNP rs75585377: P2RX2:p.Arg40Cys (chr12-132619451-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP6_Very_StrongBS1BS2

The NM_012226.5(P2RX2):c.118C>T(p.Arg40Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,612,196 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 32)

Exomes 𝑓: 0.015 ( 147 hom. )

Consequence

P2RX2
NM_012226.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.180

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_012226.5

BP6

Variant 12-132619451-C-T is Benign according to our data. Variant chr12-132619451-C-T is described in ClinVar as Benign. ClinVar VariationId is 226983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0149 (21786/1460106) while in subpopulation SAS AF = 0.0163 (1403/86248). AF 95% confidence interval is 0.0161. There are 147 homozygotes in GnomAdExome4. There are 10965 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1574 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012226.5. 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.186C>T	p.Ile62Ile	synonymous	Exon 2 of 11	NP_733782.1	Q9UBL9-1
P2RX2	NM_012226.5		c.118C>T	p.Arg40Cys	missense	Exon 2 of 9	NP_036358.2
P2RX2	NM_170683.4		c.186C>T	p.Ile62Ile	synonymous	Exon 2 of 10	NP_733783.1	Q9UBL9-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
P2RX2	ENST00000352418.8	TSL:1	c.118C>T	p.Arg40Cys	missense	Exon 2 of 9	ENSP00000341419.4	Q9UBL9-6
P2RX2	ENST00000643471.2	MANE Select	c.186C>T	p.Ile62Ile	synonymous	Exon 2 of 11	ENSP00000494644.1	Q9UBL9-1
P2RX2	ENST00000343948.8	TSL:1	c.186C>T	p.Ile62Ile	synonymous	Exon 2 of 10	ENSP00000343339.4	Q9UBL9-4

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1574

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.00661

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0112

AC:

2778

AN:

248670

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00898

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00679

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0149

AC:

21786

AN:

1460106

Hom.:

147

Cov.:

AF XY:

0.0151

AC XY:

10965

AN XY:

726432

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33426

American (AMR)

AF:

0.00980

AC:

438

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

539

AN:

26070

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39656

South Asian (SAS)

AF:

0.0163

AC:

1403

AN:

86248

European-Finnish (FIN)

AF:

0.00761

AC:

400

AN:

52534

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0163

AC:

18062

AN:

1111402

Other (OTH)

AF:

0.0132

AC:

795

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1152

2303

3455

4606

5758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

722

1444

2166

2888

3610

<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:

0.0103

AC:

1574

AN:

152090

Hom.:

Cov.:

AF XY:

0.00990

AC XY:

736

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00335

AC:

139

AN:

41528

American (AMR)

AF:

0.0124

AC:

190

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3466

East Asian (EAS)

AF:

0.000195

AC:

AN:

5132

South Asian (SAS)

AF:

0.0131

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00661

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0149

AC:

1013

AN:

67944

Other (OTH)

AF:

0.0109

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0134

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0155

AC:

133

ExAC

AF:

0.0107

AC:

1302

Asia WGS

AF:

0.00607

AC:

AN:

3472

EpiCase

AF:

0.0181

EpiControl

AF:

0.0158

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

P2RX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0073

MetaSVM

Benign

-1.1

PhyloP100

0.18

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

0.82

Vest4

0.27

ClinPred

0.037

GERP RS

0.21

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: 7

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over