chr12-21604477-T-C

Variant names:

• chr12-21604477-T-C
• rs121918423
• NM_021957.4:c.116A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_021957.4(GYS2):​c.116A>G​(p.Asn39Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000512 in 1,602,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N39K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.18
• Publications: 5 publications found

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]

GYS2 Gene-Disease associations (from GenCC):

• glycogen storage disorder due to hepatic glycogen synthase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ENSG00000285854 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 12-21604477-T-C is Pathogenic according to our data. Variant chr12-21604477-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.116A>G	p.Asn39Ser	missense_variant	Exon 1 of 16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.116A>G	p.Asn39Ser	missense_variant	Exon 1 of 17		XP_024304728.1
GYS2	XM_017019245.3	c.116A>G	p.Asn39Ser	missense_variant	Exon 1 of 9		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.116A>G	p.Asn39Ser	missense_variant	Exon 1 of 16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*124-23954A>G		intron_variant	Intron 8 of 22			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.107-23954A>G		intron_variant	Intron 1 of 10

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250680 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.0000510 AC: 74 AN: 1449938 Hom.: 0 Cov.: 29 AF XY: 0.0000512 AC XY: 37 AN XY: 722230

African (AFR) AF: 0.0000301 AC: 1 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85998

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.0000563 AC: 62 AN: 1101470

Other (OTH) AF: 0.0000334 AC: 2 AN: 59946

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency Pathogenic:4

Dec 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GYS2 c.116A>G (p.Asn39Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250680 control chromosomes (gnomAD). c.116A>G has been reported in the literature in individuals affected with Glycogen Storage Disorder Due To Hepatic Glycogen Synthase Deficiency (e.g. Orho_1998, Kamenets_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Orho_1998). The following publications have been ascertained in the context of this evaluation (PMID: 9691087, 32395408). ClinVar contains an entry for this variant (Variation ID: 16054). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.116A>G(p.Asn39Ser) variant in GYS2 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Glycogen storage disease type 0 (GSD 0) (Kamenets EA et al., 2020). This variant is reported with the allele frequency of 0.003% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. However, study in multiple affected individuals and functional evidence on its pathogenicity is not available. The amino acid Asn at position 39 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asn39Ser in GYS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 39 of the GYS2 protein (p.Asn39Ser). This variant is present in population databases (rs121918423, gnomAD 0.008%). This missense change has been observed in individual(s) with liver glycogen storage disease (PMID: 9691087, 32395408). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16054). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GYS2 protein function. Experimental studies have shown that this missense change affects GYS2 function (PMID: 9691087). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aug 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.81	P
Vest4		0.96
MutPred		0.80		Gain of catalytic residue at V41 (P = 0);
MVP		0.86
MPC		0.51
ClinPred		0.95	D
GERP RS		5.3
PromoterAI		-0.014	Neutral
Varity_R		0.54
gMVP		0.95
Mutation Taster		=45/55	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918423; hg19: chr12-21757411;