rs138461745
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002863.5(PYGL):c.1582G>A(p.Asp528Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
PYGL
NM_002863.5 missense
NM_002863.5 missense
Scores
1
8
8
Clinical Significance
Conservation
PhyloP100: 4.11
Genes affected
PYGL (HGNC:9725): (glycogen phosphorylase L) This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.23685682).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGL | NM_002863.5 | c.1582G>A | p.Asp528Asn | missense_variant | 13/20 | ENST00000216392.8 | |
PYGL | NM_001163940.2 | c.1480G>A | p.Asp494Asn | missense_variant | 12/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGL | ENST00000216392.8 | c.1582G>A | p.Asp528Asn | missense_variant | 13/20 | 1 | NM_002863.5 | P1 | |
PYGL | ENST00000532462.5 | c.1582G>A | p.Asp528Asn | missense_variant | 13/20 | 1 | |||
ENST00000557343.1 | n.244C>T | non_coding_transcript_exon_variant | 2/2 | 3 | |||||
PYGL | ENST00000544180.6 | c.1480G>A | p.Asp494Asn | missense_variant | 12/19 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251312Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135832
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461670Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727154
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GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74506
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease, type VI Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 19, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 13, 2021 | This sequence change replaces aspartic acid with asparagine at codon 528 of the PYGL protein (p.Asp528Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs138461745, ExAC 0.06%). This missense change has been observed in individual(s) with clinical features of PYGL-related conditions (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2021 | The c.1582G>A (p.D528N) alteration is located in exon 13 (coding exon 13) of the PYGL gene. This alteration results from a G to A substitution at nucleotide position 1582, causing the aspartic acid (D) at amino acid position 528 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
0.33
.;.;B
Vest4
MVP
MPC
0.11
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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