rs61733199

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.1636A>G(p.Thr546Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,605,770 control chromosomes in the GnomAD database, including 312 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T546T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 22 hom., cov: 32)

Exomes 𝑓: 0.018 ( 290 hom. )

Consequence

GYS2
NM_021957.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.595

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 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037274063).

BP6

Variant 12-21542505-T-C is Benign according to our data. Variant chr12-21542505-T-C is described in ClinVar as Benign. ClinVar VariationId is 137526.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 = 0.0144 (2199/152346) while in subpopulation NFE AF = 0.019 (1295/68022). AF 95% confidence interval is 0.0182. There are 22 homozygotes in GnomAd4. There are 1173 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4 link	c.1636A>G	p.Thr546Ala	missense_variant	Exon 13 of 16	ENST00000261195.3	NP_068776.2	P54840
GYS2	XM_024448960.2 link	c.1636A>G	p.Thr546Ala	missense_variant	Exon 13 of 17		XP_024304728.1
GYS2	XM_006719063.4 link	c.1405A>G	p.Thr469Ala	missense_variant	Exon 12 of 15		XP_006719126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GYS2	ENST00000261195.3 link	c.1636A>G	p.Thr546Ala	missense_variant	Exon 13 of 16	1	NM_021957.4	ENSP00000261195.2	P54840
ENSG00000285854	ENST00000647960.1 link	n.*1638A>G		non_coding_transcript_exon_variant	Exon 20 of 23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000647960.1 link	n.*1638A>G		3_prime_UTR_variant	Exon 20 of 23			ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2199

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0454

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0160

AC:

4020

AN:

251344

AF XY:

0.0161

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00928

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.0474

Gnomad NFE exome

AF:

0.0193

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0176

AC:

25533

AN:

1453424

Hom.:

290

Cov.:

AF XY:

0.0170

AC XY:

12335

AN XY:

723628

show subpopulations

African (AFR)

AF:

0.00255

AC:

AN:

33270

American (AMR)

AF:

0.00919

AC:

411

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0197

AC:

513

AN:

26076

East Asian (EAS)

AF:

0.00202

AC:

AN:

39672

South Asian (SAS)

AF:

0.00333

AC:

287

AN:

86126

European-Finnish (FIN)

AF:

0.0462

AC:

2466

AN:

53400

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0188

AC:

20763

AN:

1104298

Other (OTH)

AF:

0.0151

AC:

910

AN:

60120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1145

2291

3436

4582

5727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

752

1504

2256

3008

3760

<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:

0.0144

AC:

2199

AN:

152346

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1173

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00308

AC:

128

AN:

41588

American (AMR)

AF:

0.00980

AC:

150

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5192

South Asian (SAS)

AF:

0.00248

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0454

AC:

482

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0190

AC:

1295

AN:

68022

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

228

343

457

571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0170

Hom.:

105

Bravo

AF:

0.0120

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0206

AC:

177

ExAC

AF:

0.0150

AC:

1818

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0153

EpiControl

AF:

0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2014

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 07, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.19

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.29

PhyloP100

0.59

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.89

REVEL

Benign

0.023

Sift

Benign

0.38

Sift4G

Benign

0.80

Polyphen

0.0

Vest4

0.066

MPC

0.12

ClinPred

0.0020

GERP RS

0.30

Varity_R

0.068

gMVP

0.23

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over