RBCK1

RANBP2-type and C3HC4-type zinc finger containing 1, the group of Linear ubiquitin chain assembly complex |RBR E3 ubiquitin ligases|Ring finger proteins|Zinc fingers RANBP2-type

Basic information

Region (hg38): 20:407497-432139

Previous symbols: [ "C20orf18" ]

Links

ENSG00000125826 ∙ NCBI:10616 ∙ OMIM:610924 ∙ HGNC:15864 ∙ Uniprot:Q9BYM8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• polyglucosan body myopathy 1 with or without immunodeficiency (Moderate), mode of inheritance: AR
• polyglucosan body myopathy 1 with or without immunodeficiency (Strong), mode of inheritance: AR
• autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis (Supportive), mode of inheritance: AR
• polyglucosan body myopathy type 1 (Supportive), mode of inheritance: AR
• polyglucosan body myopathy 1 with or without immunodeficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Polyglucosan body myopathy 1 with or without immunodeficiency	AR	Allergy/Immunology/Infectious; Cardiovascular	Individuals have been described as being affected by recurrent and severe infections, and awareness may allow surveillance, prophylactic measures, and early and aggressive management of infections; Progressive dilated cardiomyopathy necessitating heart transplant has been described	Allergy/Immunology/Infectious; Cardiovascular; Musculoskeletal; Neurologic	23104095; 23798481; 23889995

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RBCK1 gene.

• Polyglucosan body myopathy type 1 (372 variants)
• not provided (49 variants)
• Inborn genetic diseases (21 variants)
• not specified (9 variants)
• Polyglucosan body myopathy 1 without immunodeficiency (4 variants)
• See cases (2 variants)
• Glycogen storage disease, type IV;Polyglucosan body myopathy type 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RBCK1 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				98	6	104
missense	1	1	169	3		174
nonsense	10	1				11
start loss						0
frameshift	7	3				10
inframe indel	1		5			6
splice donor/acceptor (+/-2bp)	1	2				3
splice region			11	12	1	24
non coding			2	37	35	74
Total	20	7	176	138	41

Highest pathogenic variant AF is 0.0000131

Variants in RBCK1

This is a list of pathogenic ClinVar variants found in the RBCK1 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-408274-G-C			Benign (May 22, 2021)
20-408636-G-A			Benign (May 23, 2021)
20-408749-C-A		Polyglucosan body myopathy type 1	Uncertain significance (Sep 10, 2021)
20-408762-A-G		Polyglucosan body myopathy type 1	Uncertain significance (Jun 27, 2022)
20-408769-G-A		Polyglucosan body myopathy type 1	Likely benign (Sep 03, 2023)
20-408776-A-G		Polyglucosan body myopathy type 1	Uncertain significance (Mar 13, 2022)
20-408778-A-G		Polyglucosan body myopathy type 1	Uncertain significance (Aug 04, 2023)
20-408790-G-A		Polyglucosan body myopathy type 1	Likely benign (Jan 25, 2024)
20-408796-G-C		Polyglucosan body myopathy type 1	Likely benign (Sep 27, 2022)
20-408812-C-T		Polyglucosan body myopathy type 1 • not specified	Benign (Nov 12, 2023)
20-409666-A-T			Benign (May 16, 2021)
20-409886-G-C		Polyglucosan body myopathy type 1 • Inborn genetic diseases	Uncertain significance (Sep 19, 2022)
20-409899-G-A		Polyglucosan body myopathy type 1	Uncertain significance (Jun 11, 2018)
20-409907-C-T		Polyglucosan body myopathy type 1	Pathogenic (Apr 03, 2022)
20-409908-G-A		Polyglucosan body myopathy type 1	Uncertain significance (Aug 15, 2022)
20-409917-C-T		Polyglucosan body myopathy type 1	Uncertain significance (Sep 01, 2021)
20-409921-C-T		Polyglucosan body myopathy type 1	Likely benign (Dec 08, 2021)
20-409922-G-A		Polyglucosan body myopathy type 1	Uncertain significance (Jul 25, 2022)
20-409927-T-G		Polyglucosan body myopathy type 1	Likely benign (Jan 02, 2024)
20-409929-A-C		Polyglucosan body myopathy type 1	Uncertain significance (Nov 27, 2023)
20-409940-A-G		Polyglucosan body myopathy type 1	Uncertain significance (Jul 19, 2022)
20-409952-A-G		Polyglucosan body myopathy type 1	Uncertain significance (Aug 03, 2022)
20-409958-C-T		Polyglucosan body myopathy type 1	Likely benign (Jul 25, 2022)
20-409971-G-A		Polyglucosan body myopathy type 1	Uncertain significance (Sep 01, 2021)
20-409978-CCT-C		Polyglucosan body myopathy 1 with immunodeficiency	Pathogenic (Dec 01, 2012)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RBCK1	protein_coding	protein_coding	ENST00000356286	12	23469

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.135	0.865	125730	0	18	125748	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.00	227	329	0.689	0.0000217	3293
Missense in Polyphen		28	83.505	0.33531		880
Synonymous	0.254	133	137	0.972	0.00000927	985
Loss of Function	3.92	8	31.9	0.251	0.00000172	315

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000536	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.000167	0.000163
Other	0.000654	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates. Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination. Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome. Component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF- kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. Binds polyubiquitin of different linkage types. {ECO:0000269|PubMed:12629548, ECO:0000269|PubMed:17006537, ECO:0000269|PubMed:17449468, ECO:0000269|PubMed:18711448, ECO:0000269|PubMed:19136968, ECO:0000269|PubMed:20005846, ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21455180, ECO:0000269|PubMed:21455181}.
• Disease: DISEASE: Polyglucosan body myopathy 1 with or without immunodeficiency (PGBM1) [MIM:615895]: A disease characterized by polyglucosan storage myopathy associated with early-onset progressive muscle weakness and progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. Some patients present with severe immunodeficiency, invasive bacterial infections and chronic autoinflammation. {ECO:0000269|PubMed:23104095, ECO:0000269|PubMed:23798481}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Necroptosis - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;Signal Transduction;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;TNFR1-induced NFkappaB signaling pathway;EGFR1;TNF signaling;Death Receptor Signalling;Regulation of TNFR1 signaling (Consensus)

Recessive Scores

• pRec: 0.116

Intolerance Scores

• loftool: 0.524
• rvis_EVS: -0.91
• rvis_percentile_EVS: 9.9

Haploinsufficiency Scores

• pHI: 0.198
• hipred: Y
• hipred_score: 0.625
• ghis: 0.619

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.947

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rbck1
• Phenotype: cellular phenotype; liver/biliary system phenotype

Zebrafish Information Network

• Gene name: rbck1
• Affected structure: pharyngeal arch
• Phenotype tag: abnormal
• Phenotype quality: disorganized

Gene ontology

• Biological process: protein polyubiquitination;I-kappaB kinase/NF-kappaB signaling;regulation of tumor necrosis factor-mediated signaling pathway;viral process;negative regulation of NF-kappaB transcription factor activity;positive regulation of I-kappaB kinase/NF-kappaB signaling;proteasome-mediated ubiquitin-dependent protein catabolic process;T cell receptor signaling pathway;positive regulation of NF-kappaB transcription factor activity;negative regulation of necroptotic process;protein linear polyubiquitination;positive regulation of NIK/NF-kappaB signaling;positive regulation of extrinsic apoptotic signaling pathway
• Cellular component: cytosol;LUBAC complex
• Molecular function: ubiquitin-protein transferase activity;protein binding;identical protein binding;ubiquitin binding;metal ion binding