rs121918421

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_021957.4(GYS2):c.1015G>C(p.Ala339Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,612,188 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 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

GYS2
NM_021957.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.13

Publications

8 publications found

Variant links:

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)

GYS2 links:

ENSG00000285854 (HGNC:):

ENSG00000285854 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 0.943

PP5

Variant 12-21562965-C-G is Pathogenic according to our data. Variant chr12-21562965-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16052.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 link	c.1015G>C	p.Ala339Pro	missense_variant	Exon 7 of 16	ENST00000261195.3	NP_068776.2	P54840
GYS2	XM_024448960.2 link	c.1015G>C	p.Ala339Pro	missense_variant	Exon 7 of 17		XP_024304728.1
GYS2	XM_006719063.4 link	c.784G>C	p.Ala262Pro	missense_variant	Exon 6 of 15		XP_006719126.1
GYS2	XM_017019245.3 link	c.1015G>C	p.Ala339Pro	missense_variant	Exon 7 of 9		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GYS2	ENST00000261195.3 link	c.1015G>C	p.Ala339Pro	missense_variant	Exon 7 of 16	1	NM_021957.4	ENSP00000261195.2	P54840
ENSG00000285854	ENST00000647960.1 link	n.*1017G>C		non_coding_transcript_exon_variant	Exon 14 of 23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000647960.1 link	n.*1017G>C		3_prime_UTR_variant	Exon 14 of 23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000648372.1 link	n.942G>C		non_coding_transcript_exon_variant	Exon 7 of 11

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251394

AF XY:

0.00

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1460018

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1110420

Other (OTH)

AF:

0.0000332

AC:

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency

Pathogenic:4

Jun 20, 2025

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.1015G>C (p.Ala339Pro) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 1.6e-05 in 251394 control chromosomes. c.1015G>C has been observed in individual(s) affected with Glycogen storage disease type 0 (examples,Orho_1998, Holsten_2018, Atanesyan_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 <1% of normal activity in the COS7 cells (Orho_1998). The following publications have been ascertained in the context of this evaluation (PMID: 33369375, 29167993, 9691087). ClinVar contains an entry for this variant (Variation ID: 16052). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs121918421, ExAC 0.004%). This sequence change replaces alanine with proline at codon 339 of the GYS2 protein (p.Ala339Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant has been observed in individual(s) with glycogen storage disease type 0 (PMID: 9691087, 29167993, 32395408). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 16052). Experimental studies have shown that this variant affects GYS2 protein function (PMID: 9691087). For these reasons, this variant has been classified as Pathogenic. -

Mar 16, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies found this variant is associated with significantly reduced glycogen synthase activity (Orho M et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31589614, 9691087, 32395408, 33473338, 29167993) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.085

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

3.0

PhyloP100

6.1

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.77

Sift

Uncertain

0.017

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.92

MutPred

0.84

Gain of catalytic residue at L343 (P = 0.0058);

MVP

0.94

MPC

0.60

ClinPred

0.94

GERP RS

5.1

Varity_R

0.90

gMVP

0.92

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs121918421

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over