22-21015197-C-G

Variant names:

• chr22-21015197-C-G
• rs1926112372
• NM_005446.5:c.23C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005446.5(P2RX6):​c.23C>G​(p.Ala8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: P2RX6 NM_005446.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09245175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX6	NM_005446.5	c.23C>G	p.Ala8Gly	missense_variant	Exon 1 of 12	ENST00000413302.7	NP_005437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX6	ENST00000413302.7	c.23C>G	p.Ala8Gly	missense_variant	Exon 1 of 12	1	NM_005446.5	ENSP00000416193.2
ENSG00000291240	ENST00000706202.1	n.1733-2013G>C		intron_variant	Intron 4 of 6			ENSP00000516280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1365814 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 675744

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23C>G (p.A8G) alteration is located in exon 1 (coding exon 1) of the P2RX6 gene. This alteration results from a C to G substitution at nucleotide position 23, causing the alanine (A) at amino acid position 8 to be replaced by a glycine (G). 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	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.059
Sift	Uncertain	0.011	D;T
Sift4G	Benign	0.45	T;T
Polyphen		0.27	B;.
Vest4		0.27
MutPred		0.17		Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);
MVP		0.16
MPC		0.093
ClinPred		0.17	T
GERP RS		3.5
Varity_R		0.092
gMVP		0.22

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: rs1926112372; hg19: chr22-21369486;