CUBN

cubilin

Basic information

Region (hg38): 10:16823966-17129811

Previous symbols: [ "MGA1" ]

Links

ENSG00000107611 ∙ NCBI:8029 ∙ OMIM:602997 ∙ HGNC:2548 ∙ Uniprot:O60494 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Imerslund-Grasbeck syndrome type 1 (Definitive), mode of inheritance: AR
• Imerslund-Grasbeck syndrome (Supportive), mode of inheritance: AR
• Imerslund-Grasbeck syndrome type 1 (Definitive), mode of inheritance: AR
• Imerslund-Grasbeck syndrome type 1 (Strong), mode of inheritance: AR
• proteinuria, chronic benign (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immerslund-Grasbeck syndrome 1	AR	Gastrointestinal	Early diagnosis is beneficial, as early detection may allow life-long medical treatment with parenteral hydroxocobalamin, which can ameliorate morbidity and mortality	Gastrointestinal; Hematologic; Renal	15024727; 22854512; 22929189; 30267408; 31613795
Allelic with Proteinuria, chronic benign (AR)

ClinVar

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

• Imerslund-Grasbeck syndrome (35 variants)
• not provided (5 variants)
• Imerslund-Grasbeck syndrome type 1 (5 variants)
• Imerslund-Grasbeck syndrome type 1;Proteinuria, chronic benign (3 variants)
• CUBN-related disorder (2 variants)
• Proteinuria, chronic benign;Imerslund-Grasbeck syndrome type 1 (2 variants)
• Proteinuria, chronic benign (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CUBN gene is commonly pathogenic or not.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			24	249	21	294
missense			642	48	29	719
nonsense	23	13	1			37
start loss						0
frameshift	21	7	1			29
inframe indel			2			2
splice donor/acceptor (+/-2bp)		20	2			22
splice region			21	38	5	64
non coding			38	221	191	450
Total	44	40	710	518	241

Highest pathogenic variant AF is 0.000230

Variants in CUBN

This is a list of pathogenic ClinVar variants found in the CUBN region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
10-16824035-T-C		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 12, 2018)
10-16824092-C-T		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 12, 2018)
10-16824103-A-G		Imerslund-Grasbeck syndrome type 1	Benign (Jan 13, 2018)
10-16824181-T-C		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824189-A-G		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 12, 2018)
10-16824193-C-T		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824194-G-A		Imerslund-Grasbeck syndrome type 1	Benign (Jan 13, 2018)
10-16824206-C-T		Imerslund-Grasbeck syndrome type 1	Likely benign (Jan 13, 2018)
10-16824238-A-G		Imerslund-Grasbeck syndrome type 1	Benign (Jan 12, 2018)
10-16824241-T-C		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 12, 2018)
10-16824306-G-A		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824374-T-C		Imerslund-Grasbeck syndrome type 1	Benign (Jan 12, 2018)
10-16824378-T-G		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 19, 2018)
10-16824411-C-G		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824415-G-A		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 12, 2018)
10-16824461-A-C		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824505-A-G		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 12, 2018)
10-16824515-G-T		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824522-T-C		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 12, 2018)
10-16824529-T-C		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824539-G-T		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824555-G-A		Imerslund-Grasbeck syndrome type 1	Likely benign (Jan 13, 2018)
10-16824559-C-T		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)
10-16824595-A-G		Imerslund-Grasbeck syndrome type 1	Likely benign (Jan 13, 2018)
10-16824602-C-A		Imerslund-Grasbeck syndrome type 1	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CUBN	protein_coding	protein_coding	ENST00000377833	67	305868

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.63e-42	1.00	125200	2	546	125748	0.00218

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.17	2088	1.94e+3	1.07	0.000109	23896
Missense in Polyphen		699	759.46	0.92039		9629
Synonymous	-2.05	814	743	1.10	0.0000478	6874
Loss of Function	5.62	98	179	0.547	0.00000938	2157

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00685	0.00687
Ashkenazi Jewish	0.00248	0.00248
East Asian	0.00163	0.00152
Finnish	0.00120	0.00120
European (Non-Finnish)	0.00233	0.00222
Middle Eastern	0.00163	0.00152
South Asian	0.00232	0.00219
Other	0.00196	0.00196

dbNSFP

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.
• Pathway: Vitamin digestion and absorption - Homo sapiens (human);Vitamin B12 Metabolism;Metabolism of lipids;HDL clearance;Cobalamin (Cbl, vitamin B12) transport and metabolism;Metabolism;Plasma lipoprotein clearance;Transport of small molecules;Metabolism of water-soluble vitamins and cofactors;Metabolism of steroids;Metabolism of vitamins and cofactors;Vitamin D (calciferol) metabolism;Plasma lipoprotein assembly, remodeling, and clearance;Steroid hormones (Consensus)

Recessive Scores

• pRec: 0.316

Intolerance Scores

• loftool: 0.913
• rvis_EVS: 1.26
• rvis_percentile_EVS: 93.49

Haploinsufficiency Scores

• pHI: 0.160
• hipred: N
• hipred_score: 0.425
• ghis: 0.473

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.599

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Cubn
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype; renal/urinary system phenotype

Gene ontology

• Biological process: in utero embryonic development;tissue homeostasis;thigmotaxis;receptor-mediated endocytosis;hyperosmotic response;response to nutrient;cholesterol metabolic process;adult locomotory behavior;cobalamin metabolic process;response to bacterium;cobalamin transport;endocytic hemoglobin import;high-density lipoprotein particle clearance;regulation of locomotion;vitamin D metabolic process;cobalamin catabolic process;lipoprotein transport;positive regulation of synaptic transmission, glutamatergic;protein homotrimerization
• Cellular component: lysosomal membrane;endoplasmic reticulum;Golgi apparatus;Golgi-associated vesicle;cytosol;plasma membrane;clathrin-coated pit;ionotropic glutamate receptor complex;endosome membrane;membrane;apical plasma membrane;coated vesicle;endocytic vesicle;endocytic vesicle membrane;extrinsic component of external side of plasma membrane;brush border membrane;neuron projection membrane;lysosomal lumen;synapse;extracellular exosome
• Molecular function: transporter activity;calcium ion binding;protein binding;drug binding;channel regulator activity;hemoglobin binding;cobalamin binding;signaling receptor activity;cargo receptor activity;protein homodimerization activity