GeneBe

CUBN

protein-coding

cubilin

Gene summary

Cubilin (CUBN) acts as a receptor for intrinsic factor-vitamin B12 complexes. The role of receptor is supported by the presence of 27 CUB domains. Cubulin is located within the epithelium of intestine and kidney. Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia. [provided by RefSeq, Jul 2008]

Previous symbols:
  • MGA1

MANE transcript

NM_001081.4

Inheritance

AR

ClinVar variants

P:240U:1211B:560

Top phenotype

Immerslund-Grasbeck syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr10:16,823,966-17,129,811

External References & Databases

Ensembl (ENSG00000107611)NCBI Gene (8029)OMIM (602997)HGNC:2548GenCCUniProt (O60494)AlphaFoldClinVar (CUBN)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~305.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Imerslund-Grasbeck syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009853

Submitter: Orphanet

Imerslund-Grasbeck syndrome type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100156

Submitter: Labcorp Genetics (formerly Invitae)

Imerslund-Grasbeck syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100156

Submitter: Ambry Genetics

proteinuria, chronic benignSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030042

Submitter: Labcorp Genetics (formerly Invitae)

Imerslund-Grasbeck syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100156

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.

Clinical Genomic Database (CGD)

Immerslund-Grasbeck syndrome 1AR

Manifestation: Gastrointestinal; Hematologic; Renal

Intervention: Gastrointestinal

Rationale: Early diagnosis is beneficial, as early detection may allow life-long medical treatment with parenteral hydroxocobalamin, which can ameliorate morbidity and mortality

Comments: Allelic with Proteinuria, chronic benign (AR)

Refs: 15024727; 22854512; 22929189; 30267408; 31613795Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CUBN variants in ClinVar

15 Conditions Cataloged
Imerslund-Grasbeck syndromeTotal: 1314
Imerslund-Grasbeck syndrome type 1Total: 897
Proteinuria, chronic benignTotal: 712
Inborn genetic diseasesTotal: 546
not providedTotal: 474
not specifiedTotal: 213
CUBN-related disorderTotal: 204
CUBN-related disordersTotal: 25

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001081.4. 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
2
clinvar
34
clinvar
412
clinvar
3
clinvar
 451
missense
3
clinvar
18
clinvar
1166
clinvar
130
clinvar
14
clinvar
 1331
nonsense
26
clinvar
51
clinvar
2
clinvar
 79
start loss
1
clinvar
 1
frameshift
32
clinvar
54
clinvar
4
clinvar
 90
splice donor/acceptor (+/-2bp)
3
clinvar
51
clinvar
5
clinvar
 59
Total641761211543172011

Highest pathogenic variant AF is 0.0003897063

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001081.4RefSeqNP_001072.267MANE Select
ENST00000377833.10EnsemblENSP00000367064.467MANE Select
ENST00000433666.5EnsemblENSP00000415970.15Standard
ENST00001137124.1EnsemblENSP00000810815.167Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Vitamin digestion and absorption - Homo sapiens (human)
  • Vitamin B12 Metabolism
  • Metabolism of lipids
  • HDL clearance
  • Cobalamin (Cbl, vitamin B12) transport and metabolism

Biological Process

  • in utero embryonic development
  • tissue homeostasis
  • thigmotaxis
  • receptor-mediated endocytosis
  • hyperosmotic response

Molecular Function

  • transporter activity
  • calcium ion binding
  • protein binding
  • drug binding
  • channel regulator activity

Cellular Component

  • lysosomal membrane
  • endoplasmic reticulum
  • Golgi apparatus
  • Golgi-associated vesicle
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000377833
Coding exons
67
Length
305868
Individuals with no LoFs
125200
Homozygous LoFs
2
Heterozygous LoFs
546
Defined
125748
p
0.00218
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.1720881.94e+31.070.00010923896
Missense (PolyPhen)699759.460.920399629
Synonymous-2.058147431.100.00004786874
Loss of Function5.62981790.5470.000009382157

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00530.0053notable
Latino/Admixed American0.00160.0015notable
Ashkenazi Jewish0.00250.0025notable
East Asian0.00160.0015notable
Finnish0.00120.0012notable
European (Non-Finnish)0.00230.0022notable
South Asian0.00230.0022notable
Other0.00200.0020notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Cotransporter which plays a role in lipoprotein, vitamin and iron metabolism, by facilitating their uptake. Binds to ALB, MB, Kappa and lambda-light chains, TF, hemoglobin, GC, SCGB1A1, APOA1, high density lipoprotein, and the GIF-cobalamin complex. The binding of all ligands requires calcium. Serves as important transporter in several absorptive epithelia, including intestine, renal proximal tubules and embryonic yolk sac. Interaction with LRP2 mediates its trafficking throughout vesicles and facilitates the uptake of specific ligands like GC, hemoglobin, ALB, TF and SCGB1A1. Interaction with AMN controls its trafficking to the plasma membrane and facilitates endocytosis of ligands. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface. {ECO:0000269|PubMed:10371504, ECO:0000269|PubMed:11606717, ECO:0000269|PubMed:11717447, ECO:0000269|PubMed:14576052, ECO:0000269|PubMed:9572993}.;
Disease
DISEASE: Recessive hereditary megaloblastic anemia 1 (RH-MGA1) [MIM:261100]: Due to selective malabsorption of vitamin B12. Defects in vitamin B12 absorption lead to impaired function of thymidine synthase. As a consequence DNA synthesis is interrupted. Rapidly dividing cells involved in erythropoiesis are particularly affected. {ECO:0000269|PubMed:10080186, ECO:0000269|PubMed:10887099}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.316

Intolerance Scores

LoFtool
0.913
RVIS EVS
1.26
RVIS percentile EVS
93.49

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.599

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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