Nephronophthisis 12

Summary

Nephronophthisis 12 (MONDO:0013442) is a disease caused by TTC21B (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TTC21B (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 397

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephronophthisis 12
Mondo ID	MONDO:0013442
OMIM	613820
DOID	DOID:0111119
UMLS	C3151186
MedGen	462536
GARD	0024925
Is cancer (heuristic)	no

Also known as: nephronophthisis (disease) caused by mutation in TTC21B · nephronophthisis 12 · nephronophthisis type 12 · NPHP12 · TTC21B nephronophthisis (disease)

Data availability: 397 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › nephronophthisis › nephronophthisis 12

Related subtypes (17): nephronophthisis 1, nephronophthisis 2, nephronophthisis 3, nephronophthisis 4, nephronophthisis 7, nephronophthisis-like nephropathy 1, nephronophthisis 11, nephronophthisis 9, nephronophthisis 13, nephronophthisis 14, nephronophthisis 15, nephronophthisis 16, nephronophthisis 18, nephronophthisis 19, nephronophthisis 20, late-onset nephronophthisis, nephronophthisis-like nephropathy 2

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

397 retrieved; paginated sample, class counts are floors:

226 uncertain significance, 70 conflicting classifications of pathogenicity, 27 likely benign, 22 likely pathogenic, 17 pathogenic/likely pathogenic, 17 benign, 10 benign/likely benign, 8 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070283	NM_024753.5(TTC21B):c.1546C>T (p.Gln516Ter)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1077012	NM_024753.5(TTC21B):c.497del (p.Lys166fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179040	NM_024753.5(TTC21B):c.3087del (p.Gly1030fs)	TTC21B	Pathogenic	criteria provided, single submitter
1179137	NM_024753.5(TTC21B):c.264_267dupTAGA	TTC21B	Pathogenic	criteria provided, multiple submitters, no conflicts
1224329	NM_024753.5(TTC21B):c.2741del (p.Cys914fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328343	NM_024753.5(TTC21B):c.1656_1659del (p.Leu551_Cys552insTer)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344652	NM_024753.5(TTC21B):c.1038G>A (p.Trp346Ter)	TTC21B	Pathogenic	criteria provided, single submitter
1363746	NM_024753.5(TTC21B):c.1377T>A (p.Cys459Ter)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451834	NM_024753.5(TTC21B):c.172C>T (p.Arg58Ter)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453748	NM_024753.5(TTC21B):c.2482dup (p.Met828fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1904546	NM_024753.5(TTC21B):c.1126_1127insGT (p.Asp376fs)	TTC21B	Pathogenic	criteria provided, multiple submitters, no conflicts
1944012	NM_024753.5(TTC21B):c.431del	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1983220	NM_024753.5(TTC21B):c.3130C>T (p.Arg1044Ter)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2927399	NM_024753.5(TTC21B):c.1479_1482del (p.Thr494fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2934957	NM_024753.5(TTC21B):c.1088-1G>A	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30935	NM_024753.5(TTC21B):c.626C>T (p.Pro209Leu)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30936	NM_024753.5(TTC21B):c.1656T>A (p.Cys552Ter)	TTC21B	Pathogenic	no assertion criteria provided
30937	NM_024753.5(TTC21B):c.2758-2A>G	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446649	NM_024753.5(TTC21B):c.2500C>T (p.Gln834Ter)	TTC21B	Pathogenic	criteria provided, multiple submitters, no conflicts
446650	NM_024753.5(TTC21B):c.1320del (p.Phe440fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449860	NM_024753.5(TTC21B):c.1088-1G>C	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
562402	NM_024753.5(TTC21B):c.1999C>T (p.Gln667Ter)	TTC21B	Pathogenic/Likely pathogenic	no assertion criteria provided
591254	NM_024753.5(TTC21B):c.2913dup (p.Val972fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
917962	NM_024753.5(TTC21B):c.1176_1185+1del	TTC21B	Pathogenic	no assertion criteria provided
2681765	NM_024753.5(TTC21B):c.553-2A>T	TTC21B-AS1	Pathogenic	criteria provided, single submitter
1077010	NM_024753.5(TTC21B):c.3664C>T (p.Arg1222Trp)	TTC21B	Likely pathogenic	criteria provided, single submitter
1179039	NM_024753.5(TTC21B):c.3102-2A>G	TTC21B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179100	NM_024753.5(TTC21B):c.1386+1G>T	TTC21B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179185	NM_024753.5(TTC21B):c.3340C>T (p.Gln1114Ter)	TTC21B	Likely pathogenic	criteria provided, single submitter
1473506	NM_024753.5(TTC21B):c.1087+1G>A	TTC21B	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
TTC21B	Strong	Autosomal recessive	nephronophthisis 12	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	gencc,clinvar
TTC21B-AS1	HGNC:41115	ENSG00000224490		TTC21B antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TTC21B	Tetratricopeptide repeat protein 21B	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
TTC21B-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
cerebellar hemisphere	1
right uterine tube	1
bone marrow cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
TTC21B-AS1	119	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, skeletal muscle tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTC21B	1,588
TTC21B-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTC21B	Q7Z4L5	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Intraflagellar transport	1	200.3×	0.006	TTC21B
Hedgehog ‘off’ state	1	178.4×	0.006	TTC21B

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
regulation of intraciliary retrograde transport	1	8426.0×	0.002	TTC21B
protein localization to non-motile cilium	1	4213.0×	0.002	TTC21B
negative regulation of eating behavior	1	2808.7×	0.002	TTC21B
forebrain dorsal/ventral pattern formation	1	2106.5×	0.002	TTC21B
Bergmann glial cell differentiation	1	1532.0×	0.002	TTC21B
intraciliary retrograde transport	1	1123.5×	0.002	TTC21B
cerebellar Purkinje cell differentiation	1	1053.2×	0.002	TTC21B
ventricular system development	1	842.6×	0.002	TTC21B
regulation of smoothened signaling pathway	1	624.1×	0.003	TTC21B
protein localization to cilium	1	401.2×	0.004	TTC21B
smoothened signaling pathway	1	181.2×	0.008	TTC21B
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.008	TTC21B
cilium assembly	1	73.6×	0.016	TTC21B
positive regulation of gene expression	1	38.7×	0.028	TTC21B
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TTC21B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
TTC21B	0	0
TTC21B-AS1	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	2	TTC21B, TTC21B-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TTC21B	0	—
TTC21B-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.