12-21604477-T-C

Position:

• chr12-21604477-T-C

Variant summary

Our verdict is Pathogenic. Variant got 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.18

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]

ENSG00000285854 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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. Variant chr12-21604477-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.116A>G	p.Asn39Ser	missense_variant	1/16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*124-23954A>G		intron_variant				ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.107-23954A>G		intron_variant

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

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250680 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135542

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 SAS 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

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.0000563

Gnomad4 OTH exome AF: 0.0000334

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000277 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2022	ClinVar contains an entry for this variant (Variation ID: 16054). 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. This variant is present in population databases (rs121918423, gnomAD 0.008%). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GYS2 protein function. 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. Experimental studies have shown that this missense change affects GYS2 function (PMID: 9691087). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	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. -

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
MutationTaster	Benign	1.0	A
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
Varity_R		0.54
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918423; hg19: chr12-21757411;