12-121184501-A-G

Position:

• chr12-121184501-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002562.6(P2RX7):​c.1487A>G​(p.Glu496Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E496A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: P2RX7 NM_002562.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.51

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]

P2RX7 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37982005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RX7	NM_002562.6	c.1487A>G	p.Glu496Gly	missense_variant	13/13	ENST00000328963.10	NP_002553.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10	c.1487A>G	p.Glu496Gly	missense_variant	13/13	1	NM_002562.6	ENSP00000330696.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251024 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135708

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 61 AF XY: 0.00 AC XY: 0 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.41	T
REVEL	Benign	0.23
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.27
MutPred		0.18		Loss of ubiquitination at K501 (P = 0.0464);
MVP		0.81
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3751143; hg19: chr12-121622304;