Meckel syndrome, type 6

Summary

Meckel syndrome, type 6 (MONDO:0012848) is a disease with 3 cohort genes. The dominant Reactome pathway is Anchoring of the basal body to the plasma membrane (3 cohort genes).

At a glance

• Cohort genes: 3
• ClinVar variants: 423

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meckel syndrome, type 6
Mondo ID	MONDO:0012848
MeSH	C567365
OMIM	612284
DOID	DOID:0070120
UMLS	C2676790
MedGen	382942
GARD	0015548
Is cancer (heuristic)	no

Also known as: CC2D2A Meckel syndrome · Meckel syndrome caused by mutation in CC2D2A · Meckel syndrome, type 6 · MKS6

Data availability: 423 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meckel syndrome › Meckel syndrome, type 6

Related subtypes (13): Meckel syndrome, type 1, NPHP3-related Meckel-like syndrome, Meckel syndrome, type 2, Meckel syndrome, type 3, Meckel syndrome, type 4, Meckel syndrome, type 5, Meckel syndrome, type 8, Meckel syndrome, type 10, Meckel syndrome, type 9, Meckel syndrome, type 11, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, meckel syndrome 14, Meckel syndrome 13

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

423 retrieved; paginated sample, class counts are floors:

185 uncertain significance, 97 conflicting classifications of pathogenicity, 47 pathogenic/likely pathogenic, 45 likely pathogenic, 25 pathogenic, 17 benign, 5 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074596	NM_001378615.1(CC2D2A):c.1538G>A (p.Trp513Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
126242	NM_001378615.1(CC2D2A):c.394C>T (p.Arg132Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297595	NM_001378615.1(CC2D2A):c.712G>T (p.Glu238Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322034	NM_001378615.1(CC2D2A):c.3763C>T (p.Arg1255Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395827	NM_001378615.1(CC2D2A):c.3688C>T (p.Arg1230Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1427276	NM_001378615.1(CC2D2A):c.4522del (p.Ile1508fs)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456425	NM_001378615.1(CC2D2A):c.121C>T (p.Gln41Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1554659	NM_001378615.1(CC2D2A):c.2004-17A>G	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
166801	NM_001378615.1(CC2D2A):c.1017+1G>A	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805718	NM_001378615.1(CC2D2A):c.2710G>T (p.Glu904Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1806266	NM_001378615.1(CC2D2A):c.2164G>T (p.Glu722Ter)	CC2D2A	Pathogenic	criteria provided, single submitter
1904397	NM_001378615.1(CC2D2A):c.3535G>T (p.Glu1179Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210609	NM_001378615.1(CC2D2A):c.2683C>T (p.Gln895Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210612	NM_001378615.1(CC2D2A):c.4465_4468del (p.Asp1489fs)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217597	NM_001378615.1(CC2D2A):c.3850C>T (p.Arg1284Cys)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217602	NM_001378615.1(CC2D2A):c.3055C>T (p.Arg1019Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217604	NM_001378615.1(CC2D2A):c.2999A>T (p.Glu1000Val)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217607	NM_001378615.1(CC2D2A):c.4667A>T (p.Asp1556Val)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217617	NM_001378615.1(CC2D2A):c.3975+4_3975+7del	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
217618	NM_001378615.1(CC2D2A):c.1558C>T (p.Arg520Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203534	NM_001378615.1(CC2D2A):c.2581G>A (p.Asp861Asn)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
238273	NM_001378615.1(CC2D2A):c.3652C>T (p.Arg1218Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
2573454	NM_001378615.1(CC2D2A):c.4175del (p.Pro1392fs)	CC2D2A	Pathogenic	criteria provided, single submitter
2691275	NM_001378615.1(CC2D2A):c.293_299del (p.Glu97_Phe98insTer)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
2925185	NM_001378615.1(CC2D2A):c.463C>T (p.Gln155Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2934877	NM_001378615.1(CC2D2A):c.715del (p.Met239fs)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2936760	NM_001378615.1(CC2D2A):c.4522dup (p.Ile1508fs)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2938979	NM_001080522.2(CC2D2A):c.3597_3600del	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2940749	NM_001378615.1(CC2D2A):c.2923-1G>A	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2942128	NM_001378615.1(CC2D2A):c.839del (p.Gln280fs)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCTN2	Orphanet:475	Isolated Joubert syndrome
TCTN2	Orphanet:564	Meckel syndrome
CEP290	Orphanet:110	Bardet-Biedl syndrome
CEP290	Orphanet:2318	Joubert syndrome with oculorenal defect
CEP290	Orphanet:3156	Senior-Loken syndrome
CEP290	Orphanet:564	Meckel syndrome
CEP290	Orphanet:65	Leber congenital amaurosis
CC2D2A	Orphanet:1454	Joubert syndrome with hepatic defect
CC2D2A	Orphanet:2318	Joubert syndrome with oculorenal defect
CC2D2A	Orphanet:564	Meckel syndrome
CC2D2A	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCTN2	HGNC:25774	ENSG00000168778	Q96GX1	Tectonic-2	clinvar
CEP290	HGNC:29021	ENSG00000198707	O15078	Centrosomal protein of 290 kDa	clinvar
CC2D2A	HGNC:29253	ENSG00000048342	Q9P2K1	Coiled-coil and C2 domain-containing protein 2A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCTN2	Tectonic-2	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
CEP290	Centrosomal protein of 290 kDa	Involved in early and late steps in cilia formation.
CC2D2A	Coiled-coil and C2 domain-containing protein 2A	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCTN2	Other/Unknown	no		TCTN1-3_dom, TCTN1-3, TCTN1-3_N
CEP290	Other/Unknown	no		Cep290, Cep209_CC5
CC2D2A	Protease	yes		C2_dom, CC2D2AN-C2, C2_domain_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
buccal mucosa cell	1
olfactory bulb	1
tendon of biceps brachii	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1
bronchial epithelial cell	1
bronchus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCTN2	218	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, olfactory bulb
CEP290	278	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone
CC2D2A	247	ubiquitous	marker	right uterine tube, bronchial epithelial cell, bronchus

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CEP290	2,778
TCTN2	1,254
CC2D2A	899

Intra-cohort edges

A	B	Sources
CC2D2A	CEP290	string_interaction
CC2D2A	TCTN2	intact, string_interaction
CEP290	TCTN2	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCTN2	Q96GX1	74.71
CC2D2A	Q9P2K1	69.46
CEP290	O15078	60.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring of the basal body to the plasma membrane	3	113.1×	7e-06	TCTN2, CEP290, CC2D2A
Cilium Assembly	3	108.8×	7e-06	TCTN2, CEP290, CC2D2A
Organelle biogenesis and maintenance	3	66.0×	2e-05	TCTN2, CEP290, CC2D2A
Centrosome maturation	1	84.6×	0.040	CEP290
Loss of Nlp from mitotic centrosomes	1	52.9×	0.040	CEP290
Loss of proteins required for interphase microtubule organization from the centrosome	1	52.9×	0.040	CEP290
AURKA Activation by TPX2	1	50.8×	0.040	CEP290
Recruitment of mitotic centrosome proteins and complexes	1	45.3×	0.040	CEP290
Regulation of PLK1 Activity at G2/M Transition	1	42.3×	0.040	CEP290
Mitotic G2-G2/M phases	1	42.3×	0.040	CEP290
G2/M Transition	1	42.3×	0.040	CEP290
Recruitment of NuMA to mitotic centrosomes	1	38.8×	0.040	CEP290
Mitotic Prometaphase	1	23.1×	0.061	CEP290
M Phase	1	22.0×	0.061	CEP290
Cell Cycle, Mitotic	1	16.1×	0.077	CEP290
Cell Cycle	1	12.0×	0.096	CEP290
Innate Immune System	1	8.5×	0.126	CEP290
Neutrophil degranulation	1	7.7×	0.131	CEP290
Immune System	1	4.3×	0.214	CEP290

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization to ciliary transition zone	2	1605.0×	1e-05	TCTN2, CC2D2A
cilium assembly	3	73.6×	3e-05	TCTN2, CEP290, CC2D2A
camera-type eye development	2	239.0×	2e-04	CEP290, CC2D2A
non-motile cilium assembly	2	193.7×	2e-04	CEP290, CC2D2A
smoothened signaling pathway	2	120.8×	4e-04	TCTN2, CC2D2A
kidney development	2	93.6×	6e-04	CEP290, CC2D2A
obsolete ciliary basal body-plasma membrane docking	1	2808.7×	0.001	CEP290
ciliary transition zone assembly	1	1872.4×	0.001	CEP290
pronephros development	1	802.5×	0.003	CEP290
regulation of establishment of protein localization	1	802.5×	0.003	CEP290
otic vesicle formation	1	702.2×	0.003	CEP290
hindbrain development	1	374.5×	0.005	CEP290
eye photoreceptor cell development	1	280.9×	0.006	CEP290
embryonic brain development	1	267.5×	0.006	CC2D2A
positive regulation of intracellular protein transport	1	224.7×	0.007	CEP290
motile cilium assembly	1	193.7×	0.007	CC2D2A
axoneme assembly	1	181.2×	0.007	CC2D2A
determination of left/right symmetry	1	85.1×	0.014	CC2D2A
neural tube closure	1	62.4×	0.018	CC2D2A
heart development	1	26.2×	0.041	CC2D2A
protein transport	1	14.6×	0.070	CEP290
positive regulation of DNA-templated transcription	1	9.3×	0.104	CEP290

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
TCTN2	0	0
CEP290	0	0
CC2D2A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	CC2D2A
E	Difficult family or no structure, no drug	2	TCTN2, CEP290

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TCTN2	0	—
CEP290	0	—
CC2D2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.