22-21023360-C-T

Variant names:

• chr22-21023360-C-T
• rs375848861
• NM_005446.5:c.724C>T

Variant summary

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

The NM_005446.5(P2RX6):​c.724C>T​(p.Arg242Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: P2RX6 NM_005446.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.577

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]

ENSG00000291240 (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=0.2778008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX6	NM_005446.5	c.724C>T	p.Arg242Cys	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.724C>T	p.Arg242Cys	missense_variant	Exon 7 of 12	1	NM_005446.5	ENSP00000416193.2
ENSG00000291240	ENST00000706202.1	n.1732+5976G>A		intron_variant	Intron 4 of 6			ENSP00000516280.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251158 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461694 Hom.: 0 Cov.: 35 AF XY: 0.0000261 AC XY: 19 AN XY: 727130

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74446

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000645 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.724C>T (p.R242C) alteration is located in exon 7 (coding exon 7) of the P2RX6 gene. This alteration results from a C to T substitution at nucleotide position 724, causing the arginine (R) at amino acid position 242 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.83	T;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.062	T;T
Polyphen		0.0080	B;.
Vest4		0.44
MVP		0.18
MPC		0.13
ClinPred		0.31	T
GERP RS		2.1
Varity_R		0.23
gMVP		0.65

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: rs375848861; hg19: chr22-21377649;