Seckel syndrome 2

Summary

Seckel syndrome 2 (MONDO:0011715) is a disease caused by RBBP8 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: RBBP8 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Seckel syndrome 2
Mondo ID	MONDO:0011715
MeSH	C537534
OMIM	606744
DOID	DOID:0070013
UMLS	C1847572
MedGen	338264
GARD	0015399
Is cancer (heuristic)	no

Also known as: microcephalic primordial dwarfism 2 · RBBP8 Seckel syndrome · SCKL2 · Seckel syndrome 2 · Seckel syndrome caused by mutation in RBBP8 · Seckel syndrome type 2 · Seckel-type dwarfism 2

Data availability: 19 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Seckel syndrome › Seckel syndrome 2

Related subtypes (11): Seckel syndrome 1, intrauterine growth retardation with increased mitomycin c sensitivity, Seckel syndrome 4, Seckel syndrome 5, Seckel syndrome 6, Seckel syndrome 7, Seckel syndrome 8, microcephaly 13, primary, autosomal recessive, Seckel syndrome 9, Seckel syndrome 10, Seckel syndrome 11

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

19 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 conflicting classifications of pathogenicity, 3 benign, 2 likely pathogenic, 1 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30408	NM_002894.3(RBBP8):c.2287+53T>G	RBBP8	Pathogenic	no assertion criteria provided
1683598	NM_002894.3(RBBP8):c.2048T>G (p.Leu683Ter)	RBBP8	Likely pathogenic	criteria provided, single submitter
392730	NM_002894.3(RBBP8):c.139C>T (p.Gln47Ter)	RBBP8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
127245	NM_002894.3(RBBP8):c.298C>T (p.Arg100Trp)	RBBP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130101	NM_002894.3(RBBP8):c.604+1G>T	RBBP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1447263	NM_002894.3(RBBP8):c.2024C>T (p.Thr675Ile)	RBBP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1490360	NM_002894.3(RBBP8):c.1939+20del	RBBP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436511	NM_002894.3(RBBP8):c.1223_1228del (p.Ile408_Asn409del)	RBBP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033552	NM_002894.3(RBBP8):c.2146G>A (p.Glu716Lys)	RBBP8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1368312	NM_002894.3(RBBP8):c.293A>G (p.His98Arg)	RBBP8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1413880	NM_002894.3(RBBP8):c.1243T>A (p.Ser415Thr)	RBBP8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1515094	NM_002894.3(RBBP8):c.1928A>C (p.Gln643Pro)	RBBP8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1992406	NM_002894.3(RBBP8):c.428+6T>C	RBBP8	Uncertain significance	criteria provided, single submitter
326234	NM_002894.3(RBBP8):c.2516G>A (p.Arg839Gln)	RBBP8	Uncertain significance	criteria provided, multiple submitters, no conflicts
3583189	NM_002894.3(RBBP8):c.2329G>A (p.Val777Met)	RBBP8	Uncertain significance	criteria provided, single submitter
1263878	NM_002894.3(RBBP8):c.605-48TCA[2]	RBBP8	Benign	criteria provided, multiple submitters, no conflicts
130107	NM_002894.3(RBBP8):c.2115G>A (p.Lys705=)	RBBP8	Benign	criteria provided, multiple submitters, no conflicts
326221	NM_002894.3(RBBP8):c.736C>G (p.Pro246Ala)	RBBP8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
673936	NM_002894.3(RBBP8):c.428+37T>C	RBBP8	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RBBP8	Strong	Autosomal recessive	Seckel syndrome 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RBBP8	Orphanet:313795	Jawad syndrome
RBBP8	Orphanet:808	Seckel syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RBBP8	HGNC:9891	ENSG00000101773	Q99708	DNA endonuclease RBBP8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RBBP8	DNA endonuclease RBBP8	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RBBP8	Other/Unknown	no		Ctp1_C, CtIP_N, RBBP8-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
choroid plexus epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RBBP8	273	ubiquitous	marker	choroid plexus epithelium, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RBBP8	3,235

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RBBP8	Q99708	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HDR through MMEJ (alt-NHEJ)	1	878.5×	0.005	RBBP8
Impaired BRCA2 binding to PALB2	1	456.8×	0.005	RBBP8
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.005	RBBP8
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.005	RBBP8
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.005	RBBP8
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.005	RBBP8
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.005	RBBP8
Impaired BRCA2 binding to RAD51	1	308.6×	0.005	RBBP8
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.005	RBBP8
HDR through Single Strand Annealing (SSA)	1	292.8×	0.005	RBBP8
Transcriptional Regulation by E2F6	1	292.8×	0.005	RBBP8
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.005	RBBP8
HDR through Homologous Recombination (HRR)	1	190.3×	0.007	RBBP8
Meiotic recombination	1	129.8×	0.009	RBBP8
G2/M DNA damage checkpoint	1	120.2×	0.009	RBBP8
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.009	RBBP8
Processing of DNA double-strand break ends	1	114.2×	0.009	RBBP8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA double-strand break processing involved in repair via single-strand annealing	1	2106.5×	0.002	RBBP8
DNA strand resection involved in replication fork processing	1	2106.5×	0.002	RBBP8
homologous recombination	1	1404.3×	0.002	RBBP8
mitotic G2/M transition checkpoint	1	802.5×	0.003	RBBP8
blastocyst hatching	1	543.6×	0.003	RBBP8
meiotic cell cycle	1	244.2×	0.006	RBBP8
G1/S transition of mitotic cell cycle	1	200.6×	0.006	RBBP8
double-strand break repair via homologous recombination	1	156.0×	0.007	RBBP8
cell division	1	46.2×	0.022	RBBP8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RBBP8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RBBP8

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RBBP8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.