rs2277838

Variant names:

• chr22-21023361-G-A
• rs2277838
• NM_005446.5:c.725G>A

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R242C) has been classified as Uncertain significance.

• 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
• Publications: 23 publications found

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]

P2RX6 Gene-Disease associations (from GenCC):

• myopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000291240 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
P2RX6	NM_005446.5	c.725G>A	p.Arg242His	missense_variant	Exon 7 of 12	ENST00000413302.7	NP_005437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX6	ENST00000413302.7	c.725G>A	p.Arg242His	missense_variant	Exon 7 of 12	1	NM_005446.5	ENSP00000416193.2
ENSG00000291240	ENST00000706202.1	n.1732+5975C>T		intron_variant	Intron 4 of 6			ENSP00000516280.1

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

GnomAD2 exomes AF: 0.137 AC: 34353 AN: 251132 AF XY: 0.140

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 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

African (AFR) AF: 0.0259 AC: 866 AN: 33480

American (AMR) AF: 0.0785 AC: 3509 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3479 AN: 26136

East Asian (EAS) AF: 0.0160 AC: 634 AN: 39698

South Asian (SAS) AF: 0.0879 AC: 7585 AN: 86256

European-Finnish (FIN) AF: 0.225 AC: 11984 AN: 53378

Middle Eastern (MID) AF: 0.104 AC: 597 AN: 5768

European-Non Finnish (NFE) AF: 0.187 AC: 207974 AN: 1111752

Other (OTH) AF: 0.150 AC: 9065 AN: 60370

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

African (AFR) AF: 0.0349 AC: 1451 AN: 41520

American (AMR) AF: 0.117 AC: 1791 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3472

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5180

South Asian (SAS) AF: 0.0907 AC: 437 AN: 4820

European-Finnish (FIN) AF: 0.218 AC: 2304 AN: 10556

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 13019 AN: 68004

Other (OTH) AF: 0.116 AC: 244 AN: 2110

Alfa AF: 0.166 Hom.: 7616

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;.
PhyloP100		2.3
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
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

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