Meckel syndrome, type 2

Summary

Meckel syndrome, type 2 (MONDO:0011296) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 94

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meckel syndrome, type 2
Mondo ID	MONDO:0011296
MeSH	C536131
OMIM	603194
DOID	DOID:0070116
UMLS	C1864148
MedGen	351059
GARD	0008743
Is cancer (heuristic)	no

Also known as: Meckel syndrome caused by mutation in TMEM216 · Meckel syndrome type 2 · Meckel syndrome, type 2 · Meckel-Gruber syndrome, type 2 · MKS2 · TMEM216 Meckel syndrome

Data availability: 94 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meckel syndrome › Meckel syndrome, type 2

Related subtypes (13): Meckel syndrome, type 1, NPHP3-related Meckel-like syndrome, Meckel syndrome, type 3, Meckel syndrome, type 4, Meckel syndrome, type 5, Meckel syndrome, type 6, 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

94 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 15 conflicting classifications of pathogenicity, 14 likely pathogenic, 5 benign, 5 pathogenic/likely pathogenic, 5 benign/likely benign, 3 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
197	NM_001173990.3(TMEM216):c.218G>T (p.Arg73Leu)	TMEM216	Pathogenic	criteria provided, multiple submitters, no conflicts
198	NM_001173990.3(TMEM216):c.218G>A (p.Arg73His)	TMEM216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199	NM_001173990.3(TMEM216):c.341T>G (p.Leu114Arg)	TMEM216	Pathogenic/Likely pathogenic	no assertion criteria provided
200	NM_001173990.3(TMEM216):c.230G>C (p.Gly77Ala)	TMEM216	Pathogenic/Likely pathogenic	no assertion criteria provided
217704	NM_001173990.3(TMEM216):c.398T>G (p.Leu133Ter)	TMEM216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371710	NM_001173990.3(TMEM216):c.228dup (p.Gly77fs)	TMEM216	Pathogenic	criteria provided, single submitter
56384	NM_001173990.3(TMEM216):c.253C>T (p.Arg85Ter)	TMEM216	Pathogenic	criteria provided, multiple submitters, no conflicts
591162	NM_001173990.3(TMEM216):c.67del (p.Leu23fs)	TMEM216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1494212	NM_001173990.3(TMEM216):c.229+1G>A	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599817	NM_001173990.3(TMEM216):c.230-1G>C	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599818	NM_001173990.3(TMEM216):c.246_247del (p.Cys83fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
371740	NM_001173990.3(TMEM216):c.34+2T>C	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
371759	NM_001173990.3(TMEM216):c.222del (p.Phe76fs)	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
371763	NM_001173990.3(TMEM216):c.228del (p.Phe76fs)	TMEM216	Likely pathogenic	no assertion criteria provided
371778	NM_001173990.3(TMEM216):c.35-2A>G	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
376902	NM_001173990.3(TMEM216):c.35-13_36del	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3892663	NM_001173990.3(TMEM216):c.395_398del (p.Leu132fs)	TMEM216	Likely pathogenic	criteria provided, single submitter
551831	NM_001173990.3(TMEM216):c.164_168del (p.Asn55fs)	TMEM216	Likely pathogenic	no assertion criteria provided
554706	NM_001173990.3(TMEM216):c.336C>A (p.Tyr112Ter)	TMEM216	Likely pathogenic	no assertion criteria provided
558218	NM_001173990.3(TMEM216):c.137-1G>A	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
558417	NM_001173990.3(TMEM216):c.316_317insTA (p.Tyr106fs)	TMEM216	Likely pathogenic	no assertion criteria provided
961772	NM_001173990.3(TMEM216):c.230-2A>G	TMEM216	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1645387	NM_001173990.3(TMEM216):c.34+12G>C	TMEM216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193189	NM_001173990.3(TMEM216):c.5T>C (p.Leu2Pro)	TMEM216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
257594	NM_001173990.3(TMEM216):c.*21A>G	TMEM216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2741634	NM_001173990.3(TMEM216):c.230-16G>A	TMEM216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289981	NM_001173990.3(TMEM216):c.140T>C (p.Val47Ala)	TMEM216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2906052	NM_001173990.3(TMEM216):c.137-17G>A	TMEM216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305073	NM_001173990.2(TMEM216):c.-135T>C	TMEM216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305075	NM_001173990.2(TMEM216):c.-91G>A	TMEM216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM216	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM216	Orphanet:2754	Orofaciodigital syndrome type 6
TMEM216	Orphanet:564	Meckel syndrome
TMEM216	Orphanet:791	Retinitis pigmentosa

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
TMEM216	HGNC:25018	ENSG00000187049	Q9P0N5	Transmembrane protein 216	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM216	Transmembrane protein 216	Essential for primary ciliogenesis and embryonic development, facilitating the activation of Hedgehog (Hh) signaling 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)
TMEM216	Other/Unknown	no		Uncharacterised_TM-17

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
adenohypophysis	1
pituitary gland	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM216	239	ubiquitous	marker	primordial germ cell in gonad, adenohypophysis, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM216	946

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM216	Q9P0N5	89.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Anchoring of the basal body to the plasma membrane	1	113.1×	0.009	TMEM216

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
photoreceptor cell morphogenesis	1	2808.7×	0.002	TMEM216
positive regulation of cilium assembly	1	766.0×	0.004	TMEM216
positive regulation of smoothened signaling pathway	1	421.3×	0.004	TMEM216
photoreceptor cell maintenance	1	358.6×	0.004	TMEM216
non-motile cilium assembly	1	290.6×	0.004	TMEM216
cilium assembly	1	73.6×	0.014	TMEM216

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
TMEM216	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	TMEM216

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)
TMEM216	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.