GBA2

protein-coding

glucosylceramidase beta 2, the group of Glucosylceramidases|Glycoside hydrolases

Gene summary

This gene encodes a microsomal beta-glucosidase that catalyzes the hydrolysis of bile acid 3-O-glucosides as endogenous compounds. Studies to determine subcellular localization of this protein in the liver indicated that the enzyme was mainly enriched in the microsomal fraction where it appeared to be confined to the endoplasmic reticulum. This putative transmembrane protein is thought to play a role in carbohydrate transport and metabolism. [provided by RefSeq, Jul 2008]

Previous symbols:

SPG46

MANE transcript

NM_020944.3

Inheritance

ClinVar variants

P:61U:180B:98

Top phenotype

Spastic paraplegia 46, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr9:35,736,866-35,749,228

External References & Databases

Ensembl (ENSG00000070610)

Transcript & Mutation Effects

hg38 • Region Span ~12.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015150

Submitter: ClinGen

*GBA2* was first reported in relation to autosomal recessive complex hereditary spastic paraplegia in 2010 (Boukaris et al., PMID: 20593214). The reported phenotypes include cerebellar ataxia, mental impairment (including variable intellectual disability, cognitive decline, and dementia in some patients), and early-onset cataracts. Eight variants (missense, nonsense, frameshift) that have been reported in 13 probands in 5 publications (PMIDs: 20593214, 23332916, 24252062, 23332917, 24337409) are included in this curation. While additional evidence is available in the literature, the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be loss of function (PMID: 23332916). In summary, there is definitive evidence supporting the relationship between *GBA2* and autosomal recessive complex hereditary spastic paraplegia. This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Cerebral Palsy GCEP on May 2, 2024 (SOP Version 10).

autosomal recessive cerebellar ataxia with late-onset spasticitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018129

Submitter: Orphanet

hereditary spastic paraplegia 46SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013737

Submitter: Orphanet

hereditary spastic paraplegia 46STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013737

Submitter: PanelApp Australia

hereditary spastic paraplegia 46DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013737

Submitter: G2P

hereditary spastic paraplegia 46STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013737

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spastic paraplegia 46, autosomal recessiveAR

Manifestation: Genitourinary; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 18332254; 23332916; 23332917

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GBA2 variants in ClinVar

17 Conditions Cataloged

Spastic paraplegiaTotal: 242

not providedTotal: 127

Inborn genetic diseasesTotal: 94

Hereditary spastic paraplegia 46Total: 51

not specifiedTotal: 36

Hereditary spastic paraplegiaTotal: 26

GBA2-related disorderTotal: 12

GBA2-related disordersTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020944.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	1 clinvar	70 clinvar	1 clinvar	73
missense	1 clinvar	11 clinvar	176 clinvar	23 clinvar	4 clinvar	215
nonsense	18 clinvar	4 clinvar	1 clinvar			23
start loss		1 clinvar				1
frameshift	8 clinvar	9 clinvar	1 clinvar			18
splice donor/acceptor (+/-2bp)		8 clinvar	1 clinvar			9
Total	27	34	180	93	5	339

Highest pathogenic variant AF is 0.00006976938

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020944.3	RefSeq	NP_065995.1	17	MANE Select
ENST00000378103.7	Ensembl	ENSP00000367343.3	17	MANE Select
NM_001330660.2	RefSeq	NP_001317589.1	17	Standard
ENST00000378088.1	Ensembl	ENSP00000367328.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gba2	Danio rerio	Structure: neuron Quality: truncated abnormal

Gene / Model

Organism

Observed Phenotype

gba2

Danio rerio

Structure: neuron

Quality: truncated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Other glycan degradation - Homo sapiens (human)
Sphingolipid metabolism - Homo sapiens (human)
Sphingolipid Metabolism
Metabolism of lipids
Metabolism

Biological Process

glucosylceramide catabolic process
glycosphingolipid metabolic process
central nervous system development
bile acid metabolic process
glycoside catabolic process

Molecular Function

glucosylceramidase activity
beta-glucosidase activity

Cellular Component

Golgi membrane
endoplasmic reticulum membrane
smooth endoplasmic reticulum
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378103
Coding exons: 17
Length: 13121
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.67	440	550	0.800	0.0000313	6051
Missense (PolyPhen)		121	208.43	0.58053		2354
Synonymous	0.942	184	201	0.916	0.0000105	1829
Loss of Function	1.91	39	54.2	0.719	0.00000291	531

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.00060	0.00060	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00034	0.00033	rare
South Asian	0.00042	0.00042	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-lysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide (GlcCer) to free glucose and ceramide. Involved in sphingomyelin generation and prevention of glycolipid accumulation. May also catalyze the hydrolysis of bile acid 3-O-glucosides, however, the relevance of such activity is unclear in vivo. Plays a role in central nevous system development. Required for proper formation of motor neuron axons. {ECO:0000269|PubMed:17105727, ECO:0000269|PubMed:23332916}.;

Recessive Scores

pRec: 0.194

Intolerance Scores

LoFtool: 0.161
RVIS EVS: -0.15
RVIS percentile EVS: 42.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.265

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium