chr3-81648979-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000158.4(GBE1):c.568A>G(p.Arg190Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,571,242 control chromosomes in the GnomAD database, including 75,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 6997 hom., cov: 32)

Exomes 𝑓: 0.31 ( 68475 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 3.51

Publications

44 publications found

Variant links:

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

GBE1 Gene-Disease associations (from GenCC):

glycogen storage disease due to glycogen branching enzyme deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Laboratory for Molecular Medicine, Ambry Genetics, G2P, ClinGen
adult polyglucosan body disease
Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

GBE1 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=0.002937764).

BP6

Variant 3-81648979-T-C is Benign according to our data. Variant chr3-81648979-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.568A>G	p.Arg190Gly	missense_variant	Exon 5 of 16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1 link	n.696A>G		non_coding_transcript_exon_variant	Exon 5 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GBE1	ENST00000429644.7 link	c.568A>G	p.Arg190Gly	missense_variant	Exon 5 of 16	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715.1 link	c.445A>G	p.Arg149Gly	missense_variant	Exon 5 of 16	2		ENSP00000419638.1
GBE1	ENST00000486920.1 link	n.564A>G		non_coding_transcript_exon_variant	Exon 2 of 2	3
GBE1	ENST00000498468.1 link	n.96A>G		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45374

AN:

151906

Hom.:

6994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.198

Gnomad AMR

AF:

0.259

Gnomad ASJ

AF:

0.206

Gnomad EAS

AF:

0.445

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.402

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.270

GnomAD2 exomes

AF:

0.317

AC:

70584

AN:

222350

AF XY:

0.316

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.211

Gnomad EAS exome

AF:

0.452

Gnomad FIN exome

AF:

0.412

Gnomad NFE exome

AF:

0.305

Gnomad OTH exome

AF:

0.300

GnomAD4 exome

AF:

0.306

AC:

434420

AN:

1419218

Hom.:

68475

Cov.:

AF XY:

0.305

AC XY:

215363

AN XY:

705024

show subpopulations

African (AFR)

AF:

0.275

AC:

8798

AN:

31946

American (AMR)

AF:

0.292

AC:

12046

AN:

41306

Ashkenazi Jewish (ASJ)

AF:

0.206

AC:

5287

AN:

25606

East Asian (EAS)

AF:

0.432

AC:

16756

AN:

38784

South Asian (SAS)

AF:

0.296

AC:

23806

AN:

80334

European-Finnish (FIN)

AF:

0.414

AC:

21522

AN:

52018

Middle Eastern (MID)

AF:

0.210

AC:

1196

AN:

5690

European-Non Finnish (NFE)

AF:

0.302

AC:

327313

AN:

1084656

Other (OTH)

AF:

0.301

AC:

17696

AN:

58878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

11814

23628

35443

47257

59071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10750

21500

32250

43000

53750

<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:

0.299

AC:

45395

AN:

152024

Hom.:

6997

Cov.:

AF XY:

0.303

AC XY:

22480

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.274

AC:

11370

AN:

41500

American (AMR)

AF:

0.259

AC:

3960

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.206

AC:

715

AN:

3468

East Asian (EAS)

AF:

0.444

AC:

2298

AN:

5174

South Asian (SAS)

AF:

0.311

AC:

1500

AN:

4818

European-Finnish (FIN)

AF:

0.402

AC:

4244

AN:

10552

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.302

AC:

20489

AN:

67904

Other (OTH)

AF:

0.271

AC:

572

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1622

3243

4865

6486

8108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.299

Hom.:

28517

Bravo

AF:

0.290

TwinsUK

AF:

0.309

AC:

1144

ALSPAC

AF:

0.304

AC:

1170

ESP6500AA

AF:

0.277

AC:

992

ESP6500EA

AF:

0.301

AC:

2441

ExAC

AF:

0.306

AC:

36856

Asia WGS

AF:

0.391

AC:

1360

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 30, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2015

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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Glycogen storage disease, type IV

Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Adult polyglucosan body disease

Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

3.5

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.020

D;D

Sift4G

Benign

0.066

T;T

Polyphen

0.013

B;B

Vest4

0.089

MPC

0.041

ClinPred

0.056

GERP RS

4.8

Varity_R

0.37

gMVP

0.68

Mutation Taster

=96/4

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