rs572115942
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_000294.3(PHKG2):c.926G>A(p.Arg309Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000867 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R309W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000294.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHKG2 | NM_000294.3 | c.926G>A | p.Arg309Gln | missense_variant, splice_region_variant | 9/10 | ENST00000563588.6 | |
PHKG2 | NM_001172432.2 | c.926G>A | p.Arg309Gln | missense_variant, splice_region_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHKG2 | ENST00000563588.6 | c.926G>A | p.Arg309Gln | missense_variant, splice_region_variant | 9/10 | 1 | NM_000294.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000797 AC: 20AN: 251014Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135788
GnomAD4 exome AF: 0.0000889 AC: 130AN: 1461804Hom.: 0 Cov.: 34 AF XY: 0.0000976 AC XY: 71AN XY: 727200
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74332
ClinVar
Submissions by phenotype
Mauriac syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Childrens Diabetes Center, University of Wisconsin-Madison | Jan 19, 2016 | - - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Oct 28, 2016 | - - |
Glycogen storage disease IXc Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 25, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 309 of the PHKG2 protein (p.Arg309Gln). This variant is present in population databases (rs572115942, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of glycogen storage disease (PMID: 27207549). ClinVar contains an entry for this variant (Variation ID: 253061). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PHKG2 function (PMID: 27207549). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at