rs192044702

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000158.4(GBE1):c.691+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,502,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

GBE1
NM_000158.4 splice_donor, intron

Scores

Splicing: ADA: 0.9964

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34

Conservation

PhyloP100: 8.95

Publications

16 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 3-81648854-A-G is Pathogenic according to our data. Variant chr3-81648854-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.691+2T>C		splice_donor intron	N/A	NP_000149.4	Q04446

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GBE1	ENST00000429644.7	TSL:1 MANE Select	c.691+2T>C	splice_donor intron	N/A	ENSP00000410833.2	Q04446
GBE1	ENST00000895874.1		c.691+2T>C	splice_donor intron	N/A	ENSP00000565933.1
GBE1	ENST00000942742.1		c.685+2T>C	splice_donor intron	N/A	ENSP00000612801.1

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000895

AC:

173

AN:

193326

AF XY:

0.000797

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000999

Gnomad ASJ exome

AF:

0.000259

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000971

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00103

AC:

1396

AN:

1349858

Hom.:

Cov.:

AF XY:

0.000989

AC XY:

661

AN XY:

668278

show subpopulations

African (AFR)

AF:

0.0000713

AC:

AN:

28064

American (AMR)

AF:

0.0000668

AC:

AN:

29940

Ashkenazi Jewish (ASJ)

AF:

0.000300

AC:

AN:

23344

East Asian (EAS)

AF:

0.00

AC:

AN:

36232

South Asian (SAS)

AF:

0.00

AC:

AN:

68302

European-Finnish (FIN)

AF:

0.000831

AC:

AN:

50554

Middle Eastern (MID)

AF:

0.000197

AC:

AN:

5076

European-Non Finnish (NFE)

AF:

0.00125

AC:

1314

AN:

1052456

Other (OTH)

AF:

0.000501

AC:

AN:

55890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.000756

AC:

115

AN:

152216

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

41584

American (AMR)

AF:

0.000262

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

67924

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

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:

0.000775

Hom.:

Bravo

AF:

0.000654

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00160

AC:

ExAC

AF:

0.000936

AC:

113

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (14)

Glycogen storage disease, type IV (10)

GBE1-related disorder (2)

Glycogen storage disease (2)

Adult polyglucosan body disease (1)

Arthrogryposis syndrome (1)

Dementia (1)

Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease (1)

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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

PhyloP100

8.9

GERP RS

6.1

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.69

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: 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