12-21537012-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021957.4(GYS2):c.2054T>C(p.Phe685Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00654 in 1,613,986 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. F685F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 29 hom. )

Consequence

GYS2
NM_021957.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.97

Publications

10 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 links:

ENSG00000285854 (HGNC:):

ENSG00000285854 links:

SPX (HGNC:28139): (spexin hormone) The protein encoded by this gene is a hormone involved in modulation of cardiovascular and renal function. It has also been shown in rats to cause weight loss. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

SPX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007264048).

BP6

Variant 12-21537012-A-G is Benign according to our data. Variant chr12-21537012-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00386 (587/152248) while in subpopulation NFE AF = 0.0075 (510/68018). AF 95% confidence interval is 0.00696. There are 2 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021957.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	NM_021957.4	MANE Select	c.2054T>C	p.Phe685Ser	missense	Exon 16 of 16	NP_068776.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GYS2	ENST00000261195.3	TSL:1 MANE Select	c.2054T>C	p.Phe685Ser	missense	Exon 16 of 16	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1		n.*2056T>C		non_coding_transcript_exon	Exon 23 of 23	ENSP00000497202.1
ENSG00000285854	ENST00000647960.1		n.*2056T>C		3_prime_UTR	Exon 23 of 23	ENSP00000497202.1

Frequencies

GnomAD3 genomes

AF:

0.00387

AC:

588

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00750

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00407

AC:

1022

AN:

251170

AF XY:

0.00401

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00240

Gnomad NFE exome

AF:

0.00765

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00682

AC:

9962

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00664

AC XY:

4826

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33476

American (AMR)

AF:

0.00141

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000498

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000255

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00271

AC:

145

AN:

53416

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00835

AC:

9281

AN:

1111894

Other (OTH)

AF:

0.00633

AC:

382

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

485

969

1454

1938

2423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00386

AC:

587

AN:

152248

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

255

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41540

American (AMR)

AF:

0.00105

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00750

AC:

510

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00605

Hom.:

Bravo

AF:

0.00381

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00428

AC:

520

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00632

EpiControl

AF:

0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency

Benign:4

Sep 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

not specified

Benign:2

Nov 28, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Aug 18, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GYS2: BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

GYS2-related disorder

Benign:1

Oct 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.074

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

M_CAP

Benign

0.047

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.97

PhyloP100

5.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.39

REVEL

Benign

0.20

Sift

Uncertain

0.0070

Sift4G

Benign

0.19

Polyphen

0.27

Vest4

0.47

MVP

0.76

MPC

0.38

ClinPred

0.021

GERP RS

5.5

Varity_R

0.24

gMVP

0.30

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over