rs34313873
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002863.5(PYGL):c.2416A>T(p.Ile806Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,030 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.012 ( 14 hom., cov: 32)
Exomes 𝑓: 0.017 ( 260 hom. )
Consequence
PYGL
NM_002863.5 missense
NM_002863.5 missense
Scores
2
10
4
Clinical Significance
Conservation
PhyloP100: 8.02
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.014384419).
BP6
?
Variant 14-50905520-T-A is Benign according to our data. Variant chr14-50905520-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 258841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905520-T-A is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0122 (1866/152334) while in subpopulation NFE AF= 0.0178 (1208/68026). AF 95% confidence interval is 0.0169. There are 14 homozygotes in gnomad4. There are 895 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 14 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGL | NM_002863.5 | c.2416A>T | p.Ile806Leu | missense_variant | 20/20 | ENST00000216392.8 | |
PYGL | NM_001163940.2 | c.2314A>T | p.Ile772Leu | missense_variant | 19/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGL | ENST00000216392.8 | c.2416A>T | p.Ile806Leu | missense_variant | 20/20 | 1 | NM_002863.5 | P1 | |
PYGL | ENST00000532462.5 | c.2379+2751A>T | intron_variant | 1 | |||||
PYGL | ENST00000544180.6 | c.2314A>T | p.Ile772Leu | missense_variant | 19/19 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0123 AC: 1868AN: 152216Hom.: 14 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0133 AC: 3351AN: 251450Hom.: 24 AF XY: 0.0138 AC XY: 1882AN XY: 135906
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GnomAD4 exome AF: 0.0171 AC: 24955AN: 1461696Hom.: 260 Cov.: 33 AF XY: 0.0171 AC XY: 12468AN XY: 727150
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GnomAD4 genome ? AF: 0.0122 AC: 1866AN: 152334Hom.: 14 Cov.: 32 AF XY: 0.0120 AC XY: 895AN XY: 74488
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ESP6500AA
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Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease, type VI Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 10, 2016 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PYGL: BS1, BS2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.0060
.;B
Vest4
MutPred
0.29
.;Gain of catalytic residue at I806 (P = 0.0913);
MPC
0.16
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