rs35403985

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021957.4(GYS2):c.1464A>G(p.Leu488Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,588,494 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 143 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 144 hom. )

Consequence

GYS2
NM_021957.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.364

Publications

2 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 12-21546429-T-C is Benign according to our data. Variant chr12-21546429-T-C is described in ClinVar as Benign. ClinVar VariationId is 137525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.364 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GYS2	NM_021957.4 link	c.1464A>G	p.Leu488Leu	synonymous_variant	Exon 12 of 16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2 link	c.1464A>G	p.Leu488Leu	synonymous_variant	Exon 12 of 17		XP_024304728.1
GYS2	XM_006719063.4 link	c.1233A>G	p.Leu411Leu	synonymous_variant	Exon 11 of 15		XP_006719126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GYS2	ENST00000261195.3 link	c.1464A>G	p.Leu488Leu	synonymous_variant	Exon 12 of 16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1 link	n.*1466A>G		non_coding_transcript_exon_variant	Exon 19 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000647960.1 link	n.*1466A>G		3_prime_UTR_variant	Exon 19 of 23			ENSP00000497202.1

Frequencies

GnomAD3 genomes

AF:

0.0235

AC:

3569

AN:

151700

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0805

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00833

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000625

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.00675

AC:

1684

AN:

249620

AF XY:

0.00510

show subpopulations

Gnomad AFR exome

AF:

0.0854

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000354

Gnomad OTH exome

AF:

0.00394

GnomAD4 exome

AF:

0.00279

AC:

4013

AN:

1436678

Hom.:

144

Cov.:

AF XY:

0.00249

AC XY:

1780

AN XY:

716128

show subpopulations

African (AFR)

AF:

0.0864

AC:

2849

AN:

32978

American (AMR)

AF:

0.00368

AC:

164

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.0155

AC:

401

AN:

25902

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39522

South Asian (SAS)

AF:

0.000199

AC:

AN:

85490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00631

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.000165

AC:

180

AN:

1089736

Other (OTH)

AF:

0.00613

AC:

365

AN:

59532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

169

338

508

677

846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.0235

AC:

3572

AN:

151816

Hom.:

143

Cov.:

AF XY:

0.0227

AC XY:

1687

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.0804

AC:

3325

AN:

41356

American (AMR)

AF:

0.00832

AC:

127

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000417

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000339

AC:

AN:

67942

Other (OTH)

AF:

0.0142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

164

329

493

658

822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0145

Hom.:

Bravo

AF:

0.0266

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000546

EpiControl

AF:

0.000475

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 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 08, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 12, 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

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.0

(source)

DANN

Benign

0.62

PhyloP100

-0.36

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over