rs2230911

Variant names:

• chr12-121177328-C-G
• rs2230911
• NM_002562.6:c.1070C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002562.6(P2RX7):​c.1070C>G​(p.Thr357Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 1,613,888 control chromosomes in the GnomAD database, including 10,408 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1447 hom., cov: 32)
  • Exomes 𝑓: 0.094 (8961 hom.)
• Consequence: P2RX7 NM_002562.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 87 publications found

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]

ENSG00000295862 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016603172).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX7	NM_002562.6	c.1070C>G	p.Thr357Ser	missense_variant	Exon 11 of 13	ENST00000328963.10	NP_002553.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10	c.1070C>G	p.Thr357Ser	missense_variant	Exon 11 of 13	1	NM_002562.6	ENSP00000330696.6

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18636 AN: 152080 Hom.: 1435 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.141 AC: 35513 AN: 251412 AF XY: 0.132

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.0748

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0942 AC: 137762 AN: 1461688 Hom.: 8961 Cov.: 36 AF XY: 0.0940 AC XY: 68350 AN XY: 727146

African (AFR) AF: 0.154 AC: 5156 AN: 33474

American (AMR) AF: 0.338 AC: 15130 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 1580 AN: 26134

East Asian (EAS) AF: 0.157 AC: 6246 AN: 39698

South Asian (SAS) AF: 0.151 AC: 13061 AN: 86250

European-Finnish (FIN) AF: 0.127 AC: 6780 AN: 53420

Middle Eastern (MID) AF: 0.0627 AC: 356 AN: 5676

European-Non Finnish (NFE) AF: 0.0750 AC: 83391 AN: 1111938

Other (OTH) AF: 0.100 AC: 6062 AN: 60384

GnomAD4 genome AF: 0.123 AC: 18680 AN: 152200 Hom.: 1447 Cov.: 32 AF XY: 0.127 AC XY: 9426 AN XY: 74396

African (AFR) AF: 0.158 AC: 6571 AN: 41510

American (AMR) AF: 0.221 AC: 3367 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3468

East Asian (EAS) AF: 0.166 AC: 861 AN: 5188

South Asian (SAS) AF: 0.163 AC: 786 AN: 4828

European-Finnish (FIN) AF: 0.128 AC: 1357 AN: 10588

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0774 AC: 5266 AN: 68028

Other (OTH) AF: 0.106 AC: 225 AN: 2116

Alfa AF: 0.0866 Hom.: 525

Bravo AF: 0.132

TwinsUK AF: 0.0771 AC: 286

ALSPAC AF: 0.0817 AC: 315

ESP6500AA AF: 0.158 AC: 695

ESP6500EA AF: 0.0738 AC: 635

ExAC AF: 0.132 AC: 16074

Asia WGS AF: 0.183 AC: 635 AN: 3478

EpiCase AF: 0.0672

EpiControl AF: 0.0706

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.1
PrimateAI	Benign	0.39	T
REVEL	Benign	0.10
Sift4G	Benign	0.27	T
Polyphen		0.86	P
Vest4		0.097
MutPred		0.23		Gain of catalytic residue at T357 (P = 0.0594);
ClinPred		0.021	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.38
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2230911; hg19: chr12-121615131; COSMIC: COSV55853255;