12-121165379-G-A

Variant names:

• chr12-121165379-G-A
• rs28360451
• NM_002562.6:c.556G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_002562.6(P2RX7):​c.556G>A​(p.Glu186Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,613,954 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (2 hom.)
• Consequence: P2RX7 NM_002562.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.12

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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX7	NM_002562.6	c.556G>A	p.Glu186Lys	missense_variant	Exon 6 of 13	ENST00000328963.10	NP_002553.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10	c.556G>A	p.Glu186Lys	missense_variant	Exon 6 of 13	1	NM_002562.6	ENSP00000330696.6

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251438 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 91 AN: 1461760 Hom.: 2 Cov.: 30 AF XY: 0.0000839 AC XY: 61 AN XY: 727184

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33474

Gnomad4 AMR exome AF: 0.0000447 AC: 2 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.000487 AC: 42 AN: 86252

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53386

Gnomad4 NFE exome AF: 0.0000378 AC: 42 AN: 1111928

Gnomad4 Remaining exome AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74400

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00145 AC: 0.00145048 AN: 0.00145048

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.000014705 AN: 0.000014705

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0013	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.69	T
REVEL	Uncertain	0.37
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.79		Gain of ubiquitination at E186 (P = 0.0592);
MVP		0.76
ClinPred		0.44	T
GERP RS		6.1
Varity_R		0.14
gMVP		0.92
Mutation Taster		=21/79	disease causing

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: rs28360451; hg19: chr12-121603182; COSMIC: COSV55855472; COSMIC: COSV55855472;