22-21016027-G-T

Variant names:

• chr22-21016027-G-T
• rs143057846
• NM_005446.5:c.250G>T

Variant summary

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

The NM_005446.5(P2RX6):​c.250G>T​(p.Val84Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000356 in 1,403,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V84I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: P2RX6 NM_005446.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.144
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.250G>T	p.Val84Phe	missense	Exon 2 of 12	NP_005437.2	O15547-1
	P2RX6	NM_001394691.1		c.250G>T	p.Val84Phe	missense	Exon 2 of 12	NP_001381620.1
	P2RX6	NM_001394692.1		c.250G>T	p.Val84Phe	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.250G>T	p.Val84Phe	missense	Exon 2 of 12	ENSP00000416193.2	O15547-1
	P2RX6	ENST00000401443.5	TSL:1	c.172G>T	p.Val58Phe	missense	Exon 2 of 12	ENSP00000385309.1	O15547-2
	P2RX6	ENST00000422210.5	TSL:1	n.235G>T		non_coding_transcript_exon	Exon 2 of 11	ENSP00000407920.1	H7C2V4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000597 AC: 1 AN: 167550 AF XY: 0.0000113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1403844 Hom.: 0 Cov.: 31 AF XY: 0.00000433 AC XY: 3 AN XY: 693116

African (AFR) AF: 0.00 AC: 0 AN: 31834

American (AMR) AF: 0.00 AC: 0 AN: 36498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25212

East Asian (EAS) AF: 0.00 AC: 0 AN: 36290

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4082

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1082502

Other (OTH) AF: 0.00 AC: 0 AN: 58120

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	0.015
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.14
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.16
Sift	Benign	0.40	T
Sift4G	Benign	0.51	T
Polyphen		1.0	D
Vest4		0.21
MutPred		0.46		Loss of catalytic residue at V84 (P = 0.0683)
MVP		0.12
MPC		0.38
ClinPred		0.50	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.45
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143057846; hg19: chr22-21370316;