RBBP8

RB binding protein 8, endonuclease, the group of MicroRNA protein coding host genes|BRCA1 C complex

Basic information

Region (hg38): 18:22798260-23026488

Previous symbols: [ "SCKL2" ]

Links

ENSG00000101773 ∙ NCBI:5932 ∙ OMIM:604124 ∙ HGNC:9891 ∙ Uniprot:Q99708 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Seckel syndrome (Supportive), mode of inheritance: AR
• Jawad syndrome (Supportive), mode of inheritance: AR
• Jawad syndrome (Definitive), mode of inheritance: AR
• Jawad syndrome (Strong), mode of inheritance: AR
• Seckel syndrome 2 (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Seckel syndrome 2; Jawad syndrome	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	Craniofacial; Dermatologic; Musculoskeletal; Neurologic	11781686; 18071751; 21998596; 24389050

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RBBP8 gene.

• Inborn genetic diseases (1 variants)
• Jawad syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RBBP8 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				53	5	58
missense			123	6	1	130
nonsense	1	4	2			7
start loss			1			1
frameshift	1	1	3			5
inframe indel			3			3
splice donor/acceptor (+/-2bp)		1	4	1		6
splice region			7	6		13
non coding			3	53	35	91
Total	2	6	139	113	41

Variants in RBBP8

This is a list of pathogenic ClinVar variants found in the RBBP8 region.

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

Position	Type	Phenotype	Significance	ClinVar
18-22933579-TCTCTTTAC-T			Benign (Mar 03, 2015)
18-22936411-C-A			Benign (Jun 16, 2018)
18-22936418-C-T			Benign (Jun 16, 2018)
18-22936851-G-A		not specified	Uncertain significance (Sep 22, 2016)
18-22936854-G-A			Uncertain significance (Dec 19, 2021)
18-22936857-C-T			Likely benign (Jun 27, 2022)
18-22936863-G-A			Likely benign (Jan 28, 2024)
18-22936896-T-A		Inborn genetic diseases	Uncertain significance (Apr 09, 2024)
18-22936916-A-C			Uncertain significance (Dec 19, 2023)
18-22936925-C-T			Uncertain significance (Dec 05, 2021)
18-22936944-T-C			Likely benign (Dec 31, 2019)
18-22936966-A-G		not specified • RBBP8-related disorder	Benign/Likely benign (Dec 25, 2023)
18-22936977-A-G			Uncertain significance (Feb 09, 2022)
18-22937066-G-C			Likely benign (Jul 08, 2018)
18-22937185-A-G			Likely benign (Jul 05, 2019)
18-22946144-C-T			Likely benign (Apr 20, 2019)
18-22946205-A-G			Benign (Jul 15, 2018)
18-22946270-CA-C			Likely benign (Mar 26, 2020)
18-22946424-C-CT			Benign (Dec 26, 2023)
18-22946426-T-C			Likely benign (Jan 04, 2024)
18-22946429-C-T			Likely benign (Dec 26, 2023)
18-22946440-T-G			Likely benign (Jun 27, 2022)
18-22946473-C-T		Seckel syndrome 2	Likely pathogenic (Oct 19, 2020)
18-22946487-G-A			Uncertain significance (Jul 05, 2022)
18-22946510-A-T			Benign (Jun 28, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RBBP8	protein_coding	protein_coding	ENST00000399722	18	228228

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.08e-12	0.999	125685	0	63	125748	0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0206	466	465	1.00	0.0000240	5951
Missense in Polyphen		108	113.92	0.94802		1531
Synonymous	0.0935	158	160	0.991	0.00000805	1603
Loss of Function	2.99	27	49.7	0.543	0.00000271	619

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000417	0.000416
Ashkenazi Jewish	0.00	0.00
East Asian	0.000386	0.000381
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000274	0.000273
Middle Eastern	0.000386	0.000381
South Asian	0.000392	0.000392
Other	0.000165	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in DNA-end resection, the first step of double- strand break (DSB) repair through the homologous recombination (HR) pathway. HR is restricted to S and G2 phases of the cell cycle and preferentially repairs DSBs resulting from replication fork collapse. Key determinant of DSB repair pathway choice, as it commits cells to HR by preventing classical non-homologous end- joining (NHEJ). Functions downstream of the MRN complex and ATM, promotes ATR activation and its recruitment to DSBs in the S/G2 phase facilitating the generation of ssDNA. Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage (PubMed:10764811, PubMed:10910365, PubMed:15485915, PubMed:16581787, PubMed:16818604, PubMed:17965729, PubMed:19202191, PubMed:19759395, PubMed:20064462, PubMed:20829486). During immunoglobulin heavy chain class-switch recombination, promotes microhomology-mediated alternative end joining (A-NHEJ) and plays an essential role in chromosomal translocations (By similarity). {ECO:0000250|UniProtKB:Q80YR6, ECO:0000269|PubMed:10764811, ECO:0000269|PubMed:10910365, ECO:0000269|PubMed:15485915, ECO:0000269|PubMed:16581787, ECO:0000269|PubMed:16818604, ECO:0000269|PubMed:17965729, ECO:0000269|PubMed:19202191, ECO:0000269|PubMed:19759395, ECO:0000269|PubMed:20064462, ECO:0000269|PubMed:20829486}.
• Disease: DISEASE: Seckel syndrome 2 (SCKL2) [MIM:606744]: A rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation. {ECO:0000269|PubMed:21998596, ECO:0000269|PubMed:24389050}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Jawad syndrome (JWDS) [MIM:251255]: A syndrome characterized by congenital microcephaly, moderately severe mental retardation, and symmetrical digital anomalies. Digital malformations of variable degree include hallux valgus, syndactyly of toes 4 and 5, short fifth fingers, single flexion crease of fifth fingers, polydactyly and synpolydactyly. {ECO:0000269|PubMed:21998596}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Genetic variability in RBBP8 is noted as a factor in BRCA1-associated breast cancer risk (PubMed:21799032). Associated with sensitivity to tamoxifen in certain breast cancer cell lines (PubMed:18171986). {ECO:0000269|PubMed:18171986, ECO:0000269|PubMed:21799032}.
• Pathway: Homologous recombination - Homo sapiens (human);ATM Signaling Network in Development and Disease;HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);HDR through MMEJ (alt-NHEJ);DNA Repair;Gene expression (Transcription);DNA Double-Strand Break Repair;Transcriptional Regulation by E2F6;Generic Transcription Pathway;Homology Directed Repair;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;atm signaling pathway;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Notch signaling pathway;Cell Cycle;Notch-mediated HES/HEY network;BARD1 signaling events;Processing of DNA double-strand break ends;ATM pathway;E2F transcription factor network;Presynaptic phase of homologous DNA pairing and strand exchange;Homologous DNA Pairing and Strand Exchange;Resolution of D-loop Structures through Holliday Junction Intermediates;Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA);Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR) (Consensus)

Intolerance Scores

• loftool: 0.979
• rvis_EVS: -0.64
• rvis_percentile_EVS: 16.68

Haploinsufficiency Scores

• pHI: 0.822
• hipred: Y
• hipred_score: 0.623
• ghis: 0.535

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.972

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rbbp8
• Phenotype: 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); neoplasm; embryo phenotype; cellular phenotype

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;double-strand break repair via homologous recombination;DNA double-strand break processing;blastocyst hatching;DNA replication;DNA repair;nucleotide-excision repair;regulation of transcription by RNA polymerase II;DNA double-strand break processing involved in repair via single-strand annealing;response to estradiol;cell division;meiotic cell cycle;negative regulation of G0 to G1 transition;nucleic acid phosphodiester bond hydrolysis;negative regulation of nucleic acid-templated transcription
• Cellular component: nucleus;nucleoplasm;transcriptional repressor complex;site of double-strand break;intracellular membrane-bounded organelle
• Molecular function: single-stranded DNA endodeoxyribonuclease activity;Y-form DNA binding;double-strand/single-strand DNA junction binding;RNA polymerase II repressing transcription factor binding;damaged DNA binding;double-stranded DNA binding;single-stranded DNA binding;transcription corepressor activity;protein binding;identical protein binding;flap-structured DNA binding