rs17525809

Positions:

• chr12-121154886-T-C

Variant summary

Our verdict is Benign. Variant got -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. 12/17 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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=0.0023837388).
• 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/exons	MANE	Protein	UniProt
P2RX7	NM_002562.6	c.227T>C	p.Val76Ala	missense_variant	2/13	ENST00000328963.10	NP_002553.3
LOC105370032	XR_001749352.3	n.328-28045A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10	c.227T>C	p.Val76Ala	missense_variant	2/13	1	NM_002562.6	ENSP00000330696	P1

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

GnomAD3 exomes AF: 0.0589 AC: 14803 AN: 251476 Hom.: 514 AF XY: 0.0624 AC XY: 8475 AN XY: 135910

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 SAS exome AF: 0.0801

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

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.0404

Gnomad4 ASJ exome AF: 0.0346

Gnomad4 EAS exome AF: 0.0803

Gnomad4 SAS exome AF: 0.0822

Gnomad4 FIN exome AF: 0.0537

Gnomad4 NFE exome AF: 0.0746

Gnomad4 OTH exome AF: 0.0656

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

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.0643

Gnomad4 ASJ AF: 0.0430

Gnomad4 EAS AF: 0.0554

Gnomad4 SAS AF: 0.0842

Gnomad4 FIN AF: 0.0561

Gnomad4 NFE AF: 0.0716

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0690 Hom.: 928

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
MutationTaster	Benign	1.0	N;N;N;N;N
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

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