rs786204723
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005609.4(PYGM):c.407del(p.Gly136AlafsTer159) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PYGM
NM_005609.4 frameshift
NM_005609.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.15
Genes affected
PYGM (HGNC:9726): (glycogen phosphorylase, muscle associated) This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-64758453-GC-G is Pathogenic according to our data. Variant chr11-64758453-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64758453-GC-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.407del | p.Gly136AlafsTer159 | frameshift_variant | 3/20 | ENST00000164139.4 | |
PYGM | NM_001164716.1 | c.244-188del | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.407del | p.Gly136AlafsTer159 | frameshift_variant | 3/20 | 1 | NM_005609.4 | P1 | |
PYGM | ENST00000377432.7 | c.244-188del | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251172Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135776
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461686Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727154
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 16, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Gly136Alafs*159) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs786204723, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 22250184). This variant is also known as p.G136AfsX159 (c.407G>A). ClinVar contains an entry for this variant (Variation ID: 189130). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at