rs25644

Positions:

• chr12-121228843-A-G
• chr12-121228843-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002560.3(P2RX4):​c.724A>G​(p.Ser242Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,613,984 control chromosomes in the GnomAD database, including 15,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.14 (1593 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13690 hom.)
• Consequence: P2RX4 NM_002560.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22

Genes affected

P2RX4 (HGNC:8535): (purinergic receptor P2X 4) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel with high calcium permeability. The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and PPADS. The product of this gene has the lowest sensitivity for these antagonists. Multiple alternatively spliced transcript variants, some protein-coding and some not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076737404).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RX4	NM_002560.3	c.724A>G	p.Ser242Gly	missense_variant	7/12	ENST00000337233.9	NP_002551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX4	ENST00000337233.9	c.724A>G	p.Ser242Gly	missense_variant	7/12	1	NM_002560.3	ENSP00000336607.4

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20570 AN: 152012 Hom.: 1584 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.166 AC: 41653 AN: 251448 Hom.: 4429 AF XY: 0.159 AC XY: 21571 AN XY: 135916

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.240

Gnomad SAS exome AF: 0.166

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.129 AC: 187985 AN: 1461854 Hom.: 13690 Cov.: 34 AF XY: 0.128 AC XY: 93371 AN XY: 727230

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.135 AC: 20596 AN: 152130 Hom.: 1593 Cov.: 31 AF XY: 0.140 AC XY: 10402 AN XY: 74378

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.141

Alfa AF: 0.122 Hom.: 2681

Bravo AF: 0.141

TwinsUK AF: 0.122 AC: 453

ALSPAC AF: 0.115 AC: 442

ESP6500AA AF: 0.120 AC: 529

ESP6500EA AF: 0.118 AC: 1016

ExAC AF: 0.157 AC: 19011

Asia WGS AF: 0.207 AC: 718 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.112

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.;.;.
Eigen	Benign	-0.0016
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.66	T;T;T;T;T
MetaRNN	Benign	0.0077	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N;.;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.013	D;.;D;D;D
Sift4G	Uncertain	0.023	D;D;D;T;D
Polyphen		0.087	B;.;.;.;.
Vest4		0.099
MPC		0.41
ClinPred		0.030	T
GERP RS		5.3
Varity_R		0.27
gMVP		0.66

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: rs25644; hg19: chr12-121666646; COSMIC: COSV61502287; COSMIC: COSV61502287;