NM_005446.5:c.178G>T

Variant names:

• chr22-21015955-G-T
• rs140390791
• NM_005446.5:c.178G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005446.5(P2RX6):​c.178G>T​(p.Ala60Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: P2RX6 NM_005446.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.17
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106626034).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005446.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX6	NM_005446.5	MANE Select	c.178G>T	p.Ala60Ser	missense	Exon 2 of 12	NP_005437.2	O15547-1
	P2RX6	NM_001394691.1		c.178G>T	p.Ala60Ser	missense	Exon 2 of 12	NP_001381620.1
	P2RX6	NM_001394692.1		c.178G>T	p.Ala60Ser	missense	Exon 2 of 11	NP_001381621.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX6	ENST00000413302.7	TSL:1 MANE Select	c.178G>T	p.Ala60Ser	missense	Exon 2 of 12	ENSP00000416193.2	O15547-1
	P2RX6	ENST00000401443.5	TSL:1	c.100G>T	p.Ala34Ser	missense	Exon 2 of 12	ENSP00000385309.1	O15547-2
	P2RX6	ENST00000422210.5	TSL:1	n.163G>T		non_coding_transcript_exon	Exon 2 of 11	ENSP00000407920.1	H7C2V4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397438 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31534

American (AMR) AF: 0.00 AC: 0 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078920

Other (OTH) AF: 0.00 AC: 0 AN: 57848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.93
DANN	Benign	0.92
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.53	N
PhyloP100		-1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.037
Sift	Benign	0.38	T
Sift4G	Benign	0.37	T
Polyphen		0.38	B
Vest4		0.18
MutPred		0.56		Gain of disorder (P = 0.0422)
MVP		0.13
MPC		0.17
ClinPred		0.32	T
GERP RS		-5.0
Varity_R		0.034
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs140390791; hg19: chr22-21370244;