chr12-21546416-A-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_021957.4(GYS2):c.1477T>A(p.Tyr493Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000926 in 1,597,738 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000096 ( 1 hom. )
Consequence
GYS2
NM_021957.4 missense
NM_021957.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 7.26
Genes affected
GYS2 (HGNC:4707): (glycogen synthase 2) The protein encoded by this gene, liver glycogen synthase, catalyzes the rate-limiting step in the synthesis of glycogen - the transfer of a glucose molecule from UDP-glucose to a terminal branch of the glycogen molecule. Mutations in this gene cause glycogen storage disease type 0 (GSD-0) - a rare type of early childhood fasting hypoglycemia with decreased liver glycogen content. [provided by RefSeq, Dec 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GYS2 | NM_021957.4 | c.1477T>A | p.Tyr493Asn | missense_variant | 12/16 | ENST00000261195.3 | |
GYS2 | XM_024448960.2 | c.1477T>A | p.Tyr493Asn | missense_variant | 12/17 | ||
GYS2 | XM_006719063.4 | c.1246T>A | p.Tyr416Asn | missense_variant | 11/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GYS2 | ENST00000261195.3 | c.1477T>A | p.Tyr493Asn | missense_variant | 12/16 | 1 | NM_021957.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000164 AC: 41AN: 250150Hom.: 1 AF XY: 0.000259 AC XY: 35AN XY: 135198
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GnomAD4 exome AF: 0.0000962 AC: 139AN: 1445496Hom.: 1 Cov.: 26 AF XY: 0.000142 AC XY: 102AN XY: 720120
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74452
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disorder due to hepatic glycogen synthase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 01, 2022 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 521873). This variant has not been reported in the literature in individuals affected with GYS2-related conditions. This variant is present in population databases (rs539369206, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 493 of the GYS2 protein (p.Tyr493Asn). - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0264);
MVP
MPC
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