22-21015329-A-G

Variant names:

• chr22-21015329-A-G
• rs373395002
• NM_005446.5:c.155A>G

Variant summary

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

The NM_001349876.2(P2RX6):​c.-223A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000335 in 1,551,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: P2RX6 NM_001349876.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.32
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349876.2. 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.155A>G	p.Tyr52Cys	missense	Exon 1 of 12	NP_005437.2	O15547-1
	P2RX6	NM_001349876.2		c.-223A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001336805.1
	P2RX6	NM_001349874.2		c.-291A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001336803.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX6	ENST00000413302.7	TSL:1 MANE Select	c.155A>G	p.Tyr52Cys	missense	Exon 1 of 12	ENSP00000416193.2	O15547-1
	P2RX6	ENST00000401443.5	TSL:1	c.86+69A>G		intron	N/A	ENSP00000385309.1	O15547-2
	P2RX6	ENST00000422210.5	TSL:1	n.140A>G		non_coding_transcript_exon	Exon 1 of 11	ENSP00000407920.1	H7C2V4

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151574 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000799

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000450 AC: 9 AN: 199930 AF XY: 0.0000363

Gnomad AFR exome AF: 0.000635

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: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1399608 Hom.: 0 Cov.: 32 AF XY: 0.0000201 AC XY: 14 AN XY: 695548

African (AFR) AF: 0.000415 AC: 12 AN: 28892

American (AMR) AF: 0.00 AC: 0 AN: 32910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24076

East Asian (EAS) AF: 0.00 AC: 0 AN: 34144

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5292

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087512

Other (OTH) AF: 0.0000522 AC: 3 AN: 57482

GnomAD4 genome AF: 0.000224 AC: 34 AN: 151574 Hom.: 0 Cov.: 33 AF XY: 0.000230 AC XY: 17 AN XY: 74024

African (AFR) AF: 0.000799 AC: 33 AN: 41278

American (AMR) AF: 0.0000656 AC: 1 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67926

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000332

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Benign	0.88
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		5.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.36
MPC		0.52
ClinPred		0.68	D
GERP RS		3.3
PromoterAI		-0.025	Neutral
Varity_R		0.62
gMVP		0.87
Mutation Taster		=97/103	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs373395002; hg19: chr22-21369618;