Genetic Variant P2RX7:p.Ile568Asn (chr12-121184717-T-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_002562.6(P2RX7):c.1703T>A(p.Ile568Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,562,934 control chromosomes in the GnomAD database, including 424 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 0.015 ( 24 hom., cov: 33)

Exomes 𝑓: 0.022 ( 400 hom. )

Consequence

P2RX7
NM_002562.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.96

Publications

86 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:

ENSG00000286248 (HGNC:):

ENSG00000286248 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11476803).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.015 (2289/152316) while in subpopulation NFE AF = 0.0245 (1667/68016). AF 95% confidence interval is 0.0235. There are 24 homozygotes in GnomAd4. There are 1070 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX7	NM_002562.6 link	c.1703T>A	p.Ile568Asn	missense_variant	Exon 13 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.1703T>A	p.Ile568Asn	missense_variant	Exon 13 of 13	1	NM_002562.6	ENSP00000330696.6

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2289

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00386

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0245

Gnomad OTH

AF:

0.00813

GnomAD4 exome

AF:

0.0220

AC:

31022

AN:

1410618

Hom.:

400

Cov.:

AF XY:

0.0212

AC XY:

14797

AN XY:

697236

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

31968

American (AMR)

AF:

0.00496

AC:

184

AN:

37122

Ashkenazi Jewish (ASJ)

AF:

0.00457

AC:

116

AN:

25392

East Asian (EAS)

AF:

0.0000548

AC:

AN:

36482

South Asian (SAS)

AF:

0.00329

AC:

266

AN:

80738

European-Finnish (FIN)

AF:

0.0291

AC:

1438

AN:

49482

Middle Eastern (MID)

AF:

0.000876

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0258

AC:

27995

AN:

1085258

Other (OTH)

AF:

0.0160

AC:

933

AN:

58468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.541

Heterozygous variant carriers

1905

3810

5715

7620

9525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1050

2100

3150

4200

5250

<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:

0.0150

AC:

2289

AN:

152316

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1070

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00385

AC:

160

AN:

41584

American (AMR)

AF:

0.00798

AC:

122

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0265

AC:

281

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0245

AC:

1667

AN:

68016

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

231

347

462

578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0183

Hom.:

Bravo

AF:

0.0130

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DEOGEN2

Uncertain

0.48

LIST_S2

Benign

0.85

MetaRNN

Benign

0.11

PhyloP100

3.0

Sift4G

Pathogenic

0.0010

Vest4

0.72

gMVP

0.70

Splicing

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