12-121167570-G-A

Position:

• chr12-121167570-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002562.6(P2RX7):​c.827G>A​(p.Arg276His) variant causes a missense change. The variant allele was found at a frequency of 0.0191 in 1,612,124 control chromosomes in the GnomAD database, including 371 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (27 hom., cov: 31)
  • Exomes 𝑓: 0.019 (344 hom.)
• Consequence: P2RX7 NM_002562.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61

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]

LOC105370032 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011648238).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.016 (2439/152142) while in subpopulation SAS AF= 0.0311 (150/4820). AF 95% confidence interval is 0.0271. There are 27 homozygotes in gnomad4. There are 1249 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RX7	NM_002562.6	c.827G>A	p.Arg276His	missense_variant	8/13	ENST00000328963.10	NP_002553.3
LOC105370032	XR_001749352.3	n.327+35928C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10	c.827G>A	p.Arg276His	missense_variant	8/13	1	NM_002562.6	ENSP00000330696	P1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2441 AN: 152024 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00411

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0178 AC: 4442 AN: 249296 Hom.: 59 AF XY: 0.0191 AC XY: 2576 AN XY: 134856

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.000825

Gnomad SAS exome AF: 0.0285

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0194 AC: 28300 AN: 1459982 Hom.: 344 Cov.: 32 AF XY: 0.0200 AC XY: 14492 AN XY: 726364

Gnomad4 AFR exome AF: 0.00297

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.000304

Gnomad4 SAS exome AF: 0.0274

Gnomad4 FIN exome AF: 0.0212

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0160 AC: 2439 AN: 152142 Hom.: 27 Cov.: 31 AF XY: 0.0168 AC XY: 1249 AN XY: 74376

Gnomad4 AFR AF: 0.00410

Gnomad4 AMR AF: 0.0217

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0311

Gnomad4 FIN AF: 0.0279

Gnomad4 NFE AF: 0.0203

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0189 Hom.: 78

Bravo AF: 0.0136

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0165 AC: 142

ExAC AF: 0.0174 AC: 2117

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.34	T
REVEL	Benign	0.14
Sift4G	Benign	0.17	T
Polyphen		0.95	P
Vest4		0.095
ClinPred		0.014	T
GERP RS		6.0
Varity_R		0.10
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs7958316; hg19: chr12-121605373; COSMIC: COSV55858434; COSMIC: COSV55858434;