dbSNP rs28360457: P2RX7:p.Arg307Gln (chr12-121175426-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_002562.6(P2RX7):c.920G>A(p.Arg307Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0135 in 1,599,356 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 12 hom., cov: 31)

Exomes 𝑓: 0.014 ( 185 hom. )

Consequence

P2RX7
NM_002562.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.15

Publications

84 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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor [when max_spliceai, MetaRNN, MutationTaster, PrimateAI was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0118846).

BP6

Variant 12-121175426-G-A is Benign according to our data. Variant chr12-121175426-G-A is described in ClinVar as Benign. ClinVar VariationId is 775100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0138 (19936/1447446) while in subpopulation NFE AF = 0.0163 (17875/1098784). AF 95% confidence interval is 0.0161. There are 185 homozygotes in GnomAdExome4. There are 9621 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002562.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
P2RX7	NM_002562.6	MANE Select	c.920G>A	p.Arg307Gln	missense	Exon 9 of 13	NP_002553.3
P2RX7	NR_033948.2		n.1154G>A		non_coding_transcript_exon	Exon 10 of 13
P2RX7	NR_033949.2		n.1154G>A		non_coding_transcript_exon	Exon 10 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
P2RX7	ENST00000328963.10	TSL:1 MANE Select	c.920G>A	p.Arg307Gln	missense	Exon 9 of 13	ENSP00000330696.6	Q99572-1
P2RX7	ENST00000261826.10	TSL:1	n.*373G>A		non_coding_transcript_exon	Exon 8 of 12	ENSP00000261826.6	J3KN30
P2RX7	ENST00000538011.5	TSL:1	n.*675G>A		non_coding_transcript_exon	Exon 10 of 14	ENSP00000439247.1	F5H2X6

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1576

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00274

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.00960

GnomAD2 exomes

AF:

0.00856

AC:

2152

AN:

251470

AF XY:

0.00861

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00607

Gnomad ASJ exome

AF:

0.00784

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0133

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.0138

AC:

19936

AN:

1447446

Hom.:

185

Cov.:

AF XY:

0.0133

AC XY:

9621

AN XY:

720982

show subpopulations

African (AFR)

AF:

0.00265

AC:

AN:

33214

American (AMR)

AF:

0.00693

AC:

310

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00910

AC:

237

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.000710

AC:

AN:

85972

European-Finnish (FIN)

AF:

0.0121

AC:

646

AN:

53406

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0163

AC:

17875

AN:

1098784

Other (OTH)

AF:

0.0119

AC:

710

AN:

59914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

789

1579

2368

3158

3947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.0104

AC:

1576

AN:

151910

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

750

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.00273

AC:

113

AN:

41416

American (AMR)

AF:

0.0122

AC:

186

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000831

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0168

AC:

176

AN:

10492

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1008

AN:

67980

Other (OTH)

AF:

0.00950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

168

253

337

421

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:

0.0120

Hom.:

Bravo

AF:

0.0104

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0148

AC:

127

ExAC

AF:

0.00807

AC:

980

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0122

EpiControl

AF:

0.0111

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.77

MutationAssessor

Pathogenic

3.4

PhyloP100

5.1

PrimateAI

Benign

0.48

REVEL

Uncertain

0.40

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MVP

0.82

ClinPred

0.088

GERP RS

5.6

Varity_R

0.17

gMVP

0.91

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over