rs2277838

chr22-21023361-G-A

Variant summary

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

The NM_005446.5(P2RX6):c.725G>A(p.Arg242His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,710 control chromosomes in the GnomAD database, including 24,325 homozygotes. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1763 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22562 hom.)
• Consequence: P2RX6 NM_005446.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26

Genes affected

P2RX6 (HGNC:8538): (purinergic receptor P2X 6) The protein encoded by this gene belongs to the family of P2X receptors, which are ATP-gated ion channels and mediate rapid and selective permeability to cations. This gene is predominantly expressed in skeletal muscle, and regulated by p53. The encoded protein is associated with VE-cadherin at the adherens junctions of human umbilical vein endothelial cells. Alternative splicing results in multiple transcript variants. A related pseudogene, which is also located on chromosome 22, has been identified. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026361942).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P2RX6	NM_005446.5	c.725G>A	p.Arg242His	missense_variant	7/12	ENST00000413302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P2RX6	ENST00000413302.7	c.725G>A	p.Arg242His	missense_variant	7/12	1	NM_005446.5	P1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19935 AN: 152030 Hom.: 1763 Cov.: 32

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.0906

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.117

GnomAD3 exomes AF: 0.137 AC: 34353 AN: 251132 Hom.: 3065 AF XY: 0.140 AC XY: 18938 AN XY: 135720

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.0707

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.0126

Gnomad SAS exome AF: 0.0847

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.168 AC: 245693 AN: 1461562 Hom.: 22562 Cov.: 37 AF XY: 0.167 AC XY: 121169 AN XY: 727070

Gnomad4 AFR exome AF: 0.0259

Gnomad4 AMR exome AF: 0.0785

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.0160

Gnomad4 SAS exome AF: 0.0879

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.131 AC: 19925 AN: 152148 Hom.: 1763 Cov.: 32 AF XY: 0.131 AC XY: 9721 AN XY: 74362

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.0907

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.116

Alfa AF: 0.167 Hom.: 3929

Bravo AF: 0.116

TwinsUK AF: 0.193 AC: 714

ALSPAC AF: 0.191 AC: 737

ESP6500AA AF: 0.0370 AC: 163

ESP6500EA AF: 0.183 AC: 1571

ExAC AF: 0.139 AC: 16900

Asia WGS AF: 0.0510 AC: 176 AN: 3478

EpiCase AF: 0.181

EpiControl AF: 0.176

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.73	P;P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.15
Sift	Benign	0.033	D;D
Sift4G	Benign	0.064	T;T
Polyphen		0.019	B;.
Vest4		0.21
MPC		0.19
ClinPred		0.036	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.53

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: rs2277838; hg19: chr22-21377650; COSMIC: COSV60386375; COSMIC: COSV60386375;