GBA2

glucosylceramidase beta 2, the group of Glucosylceramidases|Glycoside hydrolases

Basic information

Region (hg38): 9:35736866-35749228

Previous symbols: [ "SPG46" ]

Links

ENSG00000070610 ∙ NCBI:57704 ∙ OMIM:609471 ∙ HGNC:18986 ∙ Uniprot:Q9HCG7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 46 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 46 (Supportive), mode of inheritance: AR
• autosomal recessive cerebellar ataxia with late-onset spasticity (Supportive), mode of inheritance: AR
• hereditary spastic paraplegia 46 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paraplegia 46, autosomal recessive	AR	General	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	Genitourinary; Neurologic; Ophthalmologic	18332254; 23332916; 23332917

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GBA2 gene.

• Spastic_paraplegia (235 variants)
• not_provided (92 variants)
• Inborn_genetic_diseases (86 variants)
• Hereditary_spastic_paraplegia_46 (39 variants)
• Hereditary_spastic_paraplegia (26 variants)
• not_specified (16 variants)
• GBA2-related_disorder (8 variants)
• Neurodevelopmental_disorder (2 variants)
• Hereditary_spastic_paraplegia_5A (2 variants)
• Spastic_paraparesis (2 variants)
• Intellectual_disability (2 variants)
• Polyneuropathy (2 variants)
• Primary_dilated_cardiomyopathy (2 variants)
• CEP290-related_ciliopathy (1 variants)
• See_cases (1 variants)
• Cerebellar_ataxia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GBA2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000020944.3. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	2	65	2	70
missense	1	11	155	21	3	191
nonsense	18	3	1			22
start loss		1				1
frameshift	9	3	1			13
splice donor/acceptor (+/-2bp)		5				5
Total	28	24	159	86	5

Highest pathogenic variant AF is 0.0000697694

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GBA2	protein_coding	protein_coding	ENST00000378103	17	13121

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.99e-20	0.476	125668	0	80	125748	0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.67	440	550	0.800	0.0000313	6051
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000565	0.000564
Ashkenazi Jewish	0.000597	0.000595
East Asian	0.000326	0.000326
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.000336	0.000334
Middle Eastern	0.000326	0.000326
South Asian	0.000425	0.000425
Other	0.000163	0.000163

dbNSFP

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}.
• Pathway: Other glycan degradation - Homo sapiens (human);Sphingolipid metabolism - Homo sapiens (human);Sphingolipid Metabolism;Metabolism of lipids;Metabolism;Glycosphingolipid metabolism;Sphingolipid metabolism (Consensus)

Recessive Scores

• pRec: 0.194

Intolerance Scores

• loftool: 0.161
• rvis_EVS: -0.15
• rvis_percentile_EVS: 42.28

Haploinsufficiency Scores

• pHI: 0.116
• hipred: N
• hipred_score: 0.488
• ghis: 0.531

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.265

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gba2
• Phenotype: reproductive system phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: gba2
• Affected structure: neuron
• Phenotype tag: abnormal
• Phenotype quality: truncated

Gene ontology

• Biological process: glucosylceramide catabolic process;glycosphingolipid metabolic process;central nervous system development;bile acid metabolic process;glycoside catabolic process;central nervous system neuron development
• Cellular component: Golgi membrane;endoplasmic reticulum membrane;smooth endoplasmic reticulum;plasma membrane;integral component of membrane
• Molecular function: glucosylceramidase activity;beta-glucosidase activity