dbSNP rs28360447: P2RX7:p.Gly150Arg (chr12-121162435-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP4_StrongBS1BS2

The NM_002562.6(P2RX7):c.448G>A(p.Gly150Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,613,846 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.012 ( 15 hom., cov: 32)

Exomes 𝑓: 0.016 ( 259 hom. )

Consequence

P2RX7
NM_002562.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.12

Publications

39 publications found

Variant links:

Genes affected

P2RX7 (HGNC:8537): (purinergic receptor P2X 7) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel and is responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Activation of this nuclear receptor by ATP in the cytoplasm may be a mechanism by which cellular activity can be coupled to changes in gene expression. Multiple alternatively spliced variants have been identified, most of which fit nonsense-mediated decay (NMD) criteria. [provided by RefSeq, Jul 2010]

P2RX7 links:

ENSG00000295862 (HGNC:):

ENSG00000295862 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.015136242).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1813/152244) while in subpopulation NFE AF = 0.0181 (1233/68008). AF 95% confidence interval is 0.0173. There are 15 homozygotes in GnomAd4. There are 799 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX7	NM_002562.6 link	c.448G>A	p.Gly150Arg	missense_variant	Exon 5 of 13	ENST00000328963.10	NP_002553.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10 link	c.448G>A	p.Gly150Arg	missense_variant	Exon 5 of 13	1	NM_002562.6	ENSP00000330696.6

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1814

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.0131

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.0121

AC:

3049

AN:

251030

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00868

Gnomad ASJ exome

AF:

0.00973

Gnomad EAS exome

AF:

0.00419

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.0165

AC:

24093

AN:

1461602

Hom.:

259

Cov.:

AF XY:

0.0160

AC XY:

11606

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00326

AC:

109

AN:

33480

American (AMR)

AF:

0.00866

AC:

387

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

285

AN:

26136

East Asian (EAS)

AF:

0.00239

AC:

AN:

39698

South Asian (SAS)

AF:

0.00140

AC:

121

AN:

86238

European-Finnish (FIN)

AF:

0.0145

AC:

772

AN:

53268

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0193

AC:

21483

AN:

1111912

Other (OTH)

AF:

0.0139

AC:

837

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1240

2480

3719

4959

6199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

800

1600

2400

3200

4000

<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:

0.0119

AC:

1813

AN:

152244

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

799

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00395

AC:

164

AN:

41558

American (AMR)

AF:

0.00902

AC:

138

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3468

East Asian (EAS)

AF:

0.00425

AC:

AN:

5174

South Asian (SAS)

AF:

0.000831

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0131

AC:

139

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0181

AC:

1233

AN:

68008

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

168

251

335

419

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:

0.0159

Hom.:

Bravo

AF:

0.0116

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0181

AC:

156

ExAC

AF:

0.0126

AC:

1536

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0138

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.58

MutationAssessor

Pathogenic

3.6

PhyloP100

8.1

PrimateAI

Uncertain

0.59

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.36

MutPred

0.35

Gain of catalytic residue at G150 (P = 0.0116);

ClinPred

0.062

GERP RS

5.6

Varity_R

0.37

gMVP

0.94

Mutation Taster

=270/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over