GeneBe

MAN2B1

protein-coding

mannosidase alpha class 2B member 1, the group of Mannosidases alpha class 2

Gene summary

This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

Previous symbols:
  • MANB

MANE transcript

NM_000528.4

Inheritance

AR

ClinVar variants

P:423U:477B:571

Top phenotype

Mannosidosis, alpha B, lysosomal

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr19:12,643,831-12,666,742

External References & Databases

Ensembl (ENSG00000104774)NCBI Gene (4125)OMIM (609458)HGNC:6826GenCCUniProt (O00754)AlphaFoldClinVar (MAN2B1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~22.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

alpha-mannosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009561

Submitter: Natera

alpha-mannosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009561

Submitter: G2P

alpha-mannosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009561

Submitter: Myriad Women's Health

alpha-mannosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009561

Submitter: ClinGen

The relationship between the MAN2B1 gene and alpha-mannosidosis (MANSA), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 5, 2022. MAN2B1 encodes alpha mannosidase (PMID: 8166692), a lysosomal enzyme that is involved in the degradation of N-linked oligosaccharides via cleaving the α-mannosidic linkages (α(1 → 2), α(1 → 3) and α(1 → 6) mannosidic linkages) in high mannose and hybrid type glycans (PMID: 2338081). Individuals with alpha-mannosidosis (MANSA) show deficient alpha-mannosidase activity, leading to accumulation of undegraded N-linked oligosaccharides in lysosomes (histopathologically seen as lysosomal vacuolization) and in the urine and characteristic disease manifestations including neurologic dysfunction (mental retardation, motor deficits), coarse facial features, skeletal anomalies, and hearing deficiency (as reviewed in PMID: 18651971). The disease mechanism of MANSA is loss of function. MANSA was first reported in 1967 by Ockerman (A GENERALISED STORAGE DISORDER RESEMBLING HURLER'S SYNDROME, The Lancet, Volume 290, Issue 7509, 1967); first reports of biallelic variants in MAN2B1 among MANSA cases in 1997 by Nilssen et al. (PMID: 9158146). Both case-level (genetic) and experimental evidence support the relationship between MAN2B1 and MANSA. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 18651971, PMID: 9158146, PMID: 9758606, PMID: 9915946, PMID: 22161967). In total, ten variants from seven probands in four publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between MAN2B1 and MANSA includes: the biochemical function of the gene product (alpha-mannosidase) being consistent with the clinical and biochemical findings identified individuals with MANSA (PMID: 2338081, PMID: 18651971); the biochemical and clinical features of MAN2B1 knockout mice (PMID: 10400983); and rescue of systemic accumulation of mannose N-linked oligosaccharides via enzyme replacement therapy in MAN2B1 knockout mice (PMID: 18713755). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, MAN2B1 is definitively associated with MANSA. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9).

alpha-mannosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009561

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

alpha-mannosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009561

Submitter: PanelApp Australia

alpha-mannosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009561

Submitter: Genomics England PanelApp

alpha-mannosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009561

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mannosidosis, alpha B, lysosomalAR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical

Rationale: Manifestations can include immunodeficiency, and prophylactic vaccines and early and aggressive treatment of infections can be beneficial; Some individuals may manifest with early-onest hearing impairment, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Enzyme replacement therapy has been described as beneficial

Refs: 4358183; 995502; 724292; 6860058; 4082921; 1472354; 8357013; 7702090; 9158146; 9758606; 11014473; 15534274; 18651971; 20301570; 22161967; 29716835; 29859105; 31241255; 32331969; 33317989Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAN2B1 variants in ClinVar

9 Conditions Cataloged
Deficiency of alpha-mannosidaseTotal: 1820
not providedTotal: 188
Inborn genetic diseasesTotal: 137
not specifiedTotal: 118
MAN2B1-related disorderTotal: 81
Intellectual disabilityTotal: 5
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyTotal: 1
Craniosynostosis syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000528.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
24
clinvar
525
clinvar
8
clinvar
 558
missense
1
clinvar
42
clinvar
437
clinvar
34
clinvar
4
clinvar
 518
nonsense
38
clinvar
62
clinvar
1
clinvar
 101
start loss
2
clinvar
4
clinvar
 6
frameshift
98
clinvar
97
clinvar
2
clinvar
 197
splice donor/acceptor (+/-2bp)
10
clinvar
72
clinvar
9
clinvar
 91
Total147276477559121471

Highest pathogenic variant AF is 0.00017161458

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000528.4RefSeqNP_000519.224MANE Select
ENST00000456935.7EnsemblENSP00000395473.224MANE Select
NM_001173498.2RefSeqNP_001166969.124Standard
NM_001440570.1RefSeqNP_001427499.124Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Other glycan degradation - Homo sapiens (human)
  • Neutrophil degranulation
  • er associated degradation (erad) pathway
  • Lysosomal oligosaccharide catabolism

Biological Process

  • mannose metabolic process
  • cellular protein modification process
  • protein deglycosylation
  • oligosaccharide catabolic process
  • neutrophil degranulation

Molecular Function

  • alpha-mannosidase activity
  • carbohydrate binding
  • metal ion binding

Cellular Component

  • extracellular region
  • extracellular space
  • vacuolar membrane
  • azurophil granule lumen
  • lysosomal lumen

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000456935
Coding exons
24
Length
20232
Individuals with no LoFs
125637
Homozygous LoFs
0
Heterozygous LoFs
111
Defined
125748
p
0.000441
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.155576390.8720.00004496509
Missense (PolyPhen)199249.610.797242653
Synonymous-0.1532802771.010.00002052072
Loss of Function1.754155.00.7450.00000268568

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00110.0011notable
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish0.00130.0013notable
European (Non-Finnish)0.000460.00046rare
South Asian0.000260.00026rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover. Cleaves all known types of alpha-mannosidic linkages.;
Disease
DISEASE: Mannosidosis, alpha B, lysosomal (MANSA) [MIM:248500]: A lysosomal storage disease characterized by accumulation of unbranched oligosaccharide chains. This accumulation is expressed histologically as cytoplasmic vacuolation predominantly in the CNS and parenchymatous organs. Depending on the clinical findings at the age of onset, a severe infantile (type I) and a mild juvenile (type II) form of alpha-mannosidosis are recognized. There is considerable variation in the clinical expression with mental retardation, recurrent infections, impaired hearing and Hurler- like skeletal changes being the most consistent abnormalities. {ECO:0000269|PubMed:12718372, ECO:0000269|PubMed:15712269, ECO:0000269|PubMed:22161967, ECO:0000269|PubMed:9158146, ECO:0000269|PubMed:9758606, ECO:0000269|PubMed:9915946}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.224

Intolerance Scores

LoFtool
0.190
RVIS EVS
0.12
RVIS percentile EVS
62.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.292

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.