chr22-21016070-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005446.5(P2RX6):​c.293C>A​(p.Ala98Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,563,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

P2RX6
NM_005446.5 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
P2RX6NM_005446.5 linkc.293C>A p.Ala98Asp missense_variant Exon 2 of 12 ENST00000413302.7 NP_005437.2 O15547-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
P2RX6ENST00000413302.7 linkc.293C>A p.Ala98Asp missense_variant Exon 2 of 12 1 NM_005446.5 ENSP00000416193.2 O15547-1
ENSG00000291240ENST00000706202.1 linkn.1733-2886G>T intron_variant Intron 4 of 6 ENSP00000516280.1 A0A994J565

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000174
AC:
3
AN:
172512
Hom.:
0
AF XY:
0.0000328
AC XY:
3
AN XY:
91506
show subpopulations
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 SAS exome
AF:
0.0000426
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000287
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000220
AC:
31
AN:
1411216
Hom.:
0
Cov.:
31
AF XY:
0.0000229
AC XY:
16
AN XY:
697454
show subpopulations
Gnomad4 AFR exome
AF:
0.0000311
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000258
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000848
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.293C>A (p.A98D) alteration is located in exon 2 (coding exon 2) of the P2RX6 gene. This alteration results from a C to A substitution at nucleotide position 293, causing the alanine (A) at amino acid position 98 to be replaced by an aspartic acid (D). 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
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.030
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Pathogenic
3.3
M;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Benign
0.27
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;.
Vest4
0.84
MutPred
0.82
Gain of relative solvent accessibility (P = 0.0215);.;
MVP
0.34
MPC
0.56
ClinPred
0.90
D
GERP RS
3.3
Varity_R
0.68
gMVP
0.63

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs751001982; hg19: chr22-21370359; API