NM_000158.4:c.176T>C

Variant names:

Variant summary

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

The NM_000158.4(GBE1):c.176T>C(p.Ile59Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00827 in 1,571,730 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 64 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.79

Publications

10 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: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
adult polyglucosan body disease
Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

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=0.008882791).

BP6

Variant 3-81705581-A-G is Benign according to our data. Variant chr3-81705581-A-G is described in ClinVar as Benign. ClinVar VariationId is 255386.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 = 0.00585 (890/152224) while in subpopulation NFE AF = 0.00876 (596/68014). AF 95% confidence interval is 0.00818. There are 2 homozygotes in GnomAd4. There are 424 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_000158.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	NM_000158.4	MANE Select	c.176T>C	p.Ile59Thr	missense	Exon 2 of 16	NP_000149.4	Q04446

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBE1	ENST00000429644.7	TSL:1 MANE Select	c.176T>C	p.Ile59Thr	missense	Exon 2 of 16	ENSP00000410833.2	Q04446
GBE1	ENST00000895874.1		c.176T>C	p.Ile59Thr	missense	Exon 2 of 16	ENSP00000565933.1
GBE1	ENST00000942742.1		c.176T>C	p.Ile59Thr	missense	Exon 2 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes

AF:

0.00585

AC:

890

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00847

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00876

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00751

AC:

1426

AN:

189944

AF XY:

0.00710

show subpopulations

Gnomad AFR exome

AF:

0.00201

Gnomad AMR exome

AF:

0.0189

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00386

Gnomad NFE exome

AF:

0.00919

Gnomad OTH exome

AF:

0.00640

GnomAD4 exome

AF:

0.00853

AC:

12105

AN:

1419506

Hom.:

Cov.:

AF XY:

0.00822

AC XY:

5773

AN XY:

702562

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

32378

American (AMR)

AF:

0.0160

AC:

615

AN:

38502

Ashkenazi Jewish (ASJ)

AF:

0.00169

AC:

AN:

25386

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37948

South Asian (SAS)

AF:

0.00144

AC:

115

AN:

80024

European-Finnish (FIN)

AF:

0.00456

AC:

234

AN:

51328

Middle Eastern (MID)

AF:

0.00228

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00970

AC:

10567

AN:

1089460

Other (OTH)

AF:

0.00801

AC:

471

AN:

58778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

534

1069

1603

2138

2672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

400

800

1200

1600

2000

<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:

0.00585

AC:

890

AN:

152224

Hom.:

Cov.:

AF XY:

0.00570

AC XY:

424

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41568

American (AMR)

AF:

0.00846

AC:

129

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00876

AC:

596

AN:

68014

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00791

Hom.:

Bravo

AF:

0.00605

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00301

AC:

ESP6500EA

AF:

0.00797

AC:

ExAC

AF:

0.00532

AC:

637

Asia WGS

AF:

0.00144

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Glycogen storage disease, type IV (2)

not specified (2)

Adult polyglucosan body disease (1)

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.8

PhyloP100

7.8

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.44

Sift

Benign

0.034

Sift4G

Uncertain

0.029

Polyphen

0.77

Vest4

0.75

MVP

0.55

MPC

0.078

ClinPred

0.034

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.84

Mutation Taster

=15/85

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over