GeneBe

RBBP8

protein-coding

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

Gene summary

The protein encoded by this gene is a ubiquitously expressed nuclear protein. It is found among several proteins that bind directly to retinoblastoma protein, which regulates cell proliferation. This protein complexes with transcriptional co-repressor CTBP. It is also associated with BRCA1 and is thought to modulate the functions of BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control. It is suggested that this gene may itself be a tumor suppressor acting in the same pathway as BRCA1. Three transcript variants encoding two different isoforms have been found for this gene. More transcript variants exist, but their full-length natures have not been determined. [provided by RefSeq, Jul 2008]

Previous symbols:
  • SCKL2

MANE transcript

NM_002894.3

Inheritance

AR

ClinVar variants

P:17U:208B:104

Top phenotype

Seckel syndrome 2; Jawad syndrome

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr18:22,798,261-23,026,488

External References & Databases

Ensembl (ENSG00000101773)NCBI Gene (5932)OMIM (604124)HGNC:9891GenCCUniProt (Q99708)AlphaFoldClinVar (RBBP8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~228.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Jawad syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009622

Submitter: G2P

Seckel syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011715

Submitter: Ambry Genetics

Jawad syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009622

Submitter: Orphanet

Jawad syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009622

Submitter: PanelApp Australia

Seckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019342

Submitter: Orphanet

Jawad syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009622

Submitter: Labcorp Genetics (formerly Invitae)

Seckel syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011715

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Seckel syndrome 2; Jawad syndromeAR

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 11781686; 18071751; 21998596; 24389050Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RBBP8 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 308
Inborn genetic diseasesTotal: 116
not specifiedTotal: 53
RBBP8-related disorderTotal: 20
Jawad syndromeTotal: 20
Seckel syndrome 2Total: 18
Carcinoma of pancreasTotal: 1
MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002894.3. 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
86
clinvar
2
clinvar
 89
missense
1
clinvar
193
clinvar
15
clinvar
1
clinvar
 210
nonsense
1
clinvar
5
clinvar
1
clinvar
 7
start loss
1
clinvar
 1
frameshift
2
clinvar
5
clinvar
3
clinvar
 10
splice donor/acceptor (+/-2bp)
3
clinvar
9
clinvar
 12
Total3142081013329

Highest pathogenic variant AF is 0.00010099958

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002894.3RefSeqNP_002885.118MANE Select
ENST00000327155.10EnsemblENSP00000323050.518MANE Select
NM_203291.2RefSeqNP_976036.118Standard
NM_203292.2RefSeqNP_976037.117Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

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

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

Cellular Component

  • nucleus
  • nucleoplasm
  • transcriptional repressor complex
  • site of double-strand break
  • intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000399722
Coding exons
18
Length
228228
Individuals with no LoFs
125685
Homozygous LoFs
0
Heterozygous LoFs
63
Defined
125748
p
0.000251
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.02064664651.000.00002405951
Missense (PolyPhen)108113.920.948021531
Synonymous0.09351581600.9910.000008051603
Loss of Function2.992749.70.5430.00000271619

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American0.000230.00023rare
Ashkenazi Jewish00.0absent
East Asian0.000390.00038rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000270.00027rare
South Asian0.000390.00039rare
Other0.000170.00016rare

dbNSFP Gene Annotations

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}.;

Intolerance Scores

LoFtool
0.979
RVIS EVS
-0.64
RVIS percentile EVS
16.68

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.972

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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