rs17525809

Variant names:

• chr12-121154886-T-C
• rs17525809
• NM_002562.6:c.227T>C

Variant summary

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

The NM_002562.6(P2RX7):​c.227T>C​(p.Val76Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0691 in 1,613,982 control chromosomes in the GnomAD database, including 4,300 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V76M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (260 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4040 hom.)
• Consequence: P2RX7 NM_002562.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 63 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]

LOC105370032 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023837388).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX7	NM_002562.6	c.227T>C	p.Val76Ala	missense_variant	Exon 2 of 13	ENST00000328963.10	NP_002553.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10	c.227T>C	p.Val76Ala	missense_variant	Exon 2 of 13	1	NM_002562.6	ENSP00000330696.6

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8085 AN: 152148 Hom.: 260 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.0549

Gnomad SAS AF: 0.0835

Gnomad FIN AF: 0.0561

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0715

Gnomad OTH AF: 0.0598

GnomAD2 exomes AF: 0.0589 AC: 14803 AN: 251476 AF XY: 0.0624

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0352

Gnomad EAS exome AF: 0.0426

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0718

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0708 AC: 103505 AN: 1461716 Hom.: 4040 Cov.: 32 AF XY: 0.0718 AC XY: 52186 AN XY: 727148

African (AFR) AF: 0.0102 AC: 341 AN: 33480

American (AMR) AF: 0.0404 AC: 1808 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 904 AN: 26134

East Asian (EAS) AF: 0.0803 AC: 3188 AN: 39698

South Asian (SAS) AF: 0.0822 AC: 7094 AN: 86254

European-Finnish (FIN) AF: 0.0537 AC: 2866 AN: 53420

Middle Eastern (MID) AF: 0.0692 AC: 399 AN: 5768

European-Non Finnish (NFE) AF: 0.0746 AC: 82941 AN: 1111846

Other (OTH) AF: 0.0656 AC: 3964 AN: 60392

GnomAD4 genome AF: 0.0531 AC: 8089 AN: 152266 Hom.: 260 Cov.: 32 AF XY: 0.0531 AC XY: 3956 AN XY: 74458

African (AFR) AF: 0.0139 AC: 576 AN: 41568

American (AMR) AF: 0.0643 AC: 983 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 149 AN: 3466

East Asian (EAS) AF: 0.0554 AC: 287 AN: 5176

South Asian (SAS) AF: 0.0842 AC: 406 AN: 4824

European-Finnish (FIN) AF: 0.0561 AC: 596 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0716 AC: 4866 AN: 68006

Other (OTH) AF: 0.0587 AC: 124 AN: 2112

Alfa AF: 0.0663 Hom.: 1187

Bravo AF: 0.0511

TwinsUK AF: 0.0690 AC: 256

ALSPAC AF: 0.0760 AC: 293

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0697 AC: 599

ExAC AF: 0.0597 AC: 7249

Asia WGS AF: 0.0580 AC: 200 AN: 3478

EpiCase AF: 0.0751

EpiControl AF: 0.0756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.37
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.4
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.39	T
Polyphen		0.019	B
Vest4		0.025
ClinPred		0.0019	T
GERP RS		-4.0
Varity_R		0.025
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17525809; hg19: chr12-121592689; COSMIC: COSV55854295;