chr12-121177328-C-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 11/18 in silico tools predict 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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=0.0016603172).
• 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

GnomAD3 exomes AF: 0.141 AC: 35513 AN: 251412 Hom.: 3906 AF XY: 0.132 AC XY: 17941 AN XY: 135888

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 SAS exome AF: 0.156

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

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.0605

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.151

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.0750

Gnomad4 OTH exome AF: 0.100

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

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.0774

Gnomad4 OTH AF: 0.106

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
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

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

Publications

LitVar

Other links and lift over

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