TTC21B

tetratricopeptide repeat domain 21B, the group of IFT-A complex|Tetratricopeptide repeat domain containing

Basic information

Region (hg38): 2:165857474-165953851

Links

ENSG00000123607 ∙ NCBI:79809 ∙ OMIM:612014 ∙ HGNC:25660 ∙ Uniprot:Q7Z4L5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• asphyxiating thoracic dystrophy 4 (Definitive), mode of inheritance: AR
• Jeune syndrome (Supportive), mode of inheritance: AR
• nephronophthisis 2 (Supportive), mode of inheritance: AR
• asphyxiating thoracic dystrophy 4 (Strong), mode of inheritance: AR
• nephronophthisis 12 (Strong), mode of inheritance: AR
• nephronophthisis 12 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Nephronophthisis 12; Short-rib thoracic dysplasia 4 with or without polydactyly	AR	General	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	Musculoskeletal; Neurologic; Ophthalmologic; Renal	20301500; 21258341
The condition may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TTC21B gene.

• Jeune thoracic dystrophy;Nephronophthisis (586 variants)
• not provided (255 variants)
• Nephronophthisis;Jeune thoracic dystrophy (254 variants)
• Nephronophthisis 12 (135 variants)
• Asphyxiating thoracic dystrophy 4 (127 variants)
• Asphyxiating thoracic dystrophy 4;Nephronophthisis 12 (101 variants)
• not specified (58 variants)
• Inborn genetic diseases (49 variants)
• Nephronophthisis 12;Asphyxiating thoracic dystrophy 4 (30 variants)
• Connective tissue disorder (24 variants)
• Jeune thoracic dystrophy (15 variants)
• TTC21B-related condition (12 variants)
• Familial aplasia of the vermis (10 variants)
• Nephrotic syndrome (4 variants)
• Joubert syndrome 1 (3 variants)
• Nephronophthisis (2 variants)
• TTC21B-Related Disorders (2 variants)
• Infantile nephronophthisis (2 variants)
• Renal dysplasia and retinal aplasia (2 variants)
• Retinal dystrophy (2 variants)
• Bardet-Biedl syndrome 2 (1 variants)
• Finnish congenital nephrotic syndrome (1 variants)
• See cases (1 variants)
• Type IV short rib polydactyly syndrome (1 variants)
• Chronic kidney disease (1 variants)
• Meckel-Gruber-like syndrome (1 variants)
• Short-rib thoracic dysplasia 6 with or without polydactyly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TTC21B gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			12	167	5	184
missense		3	440	6	5	454
nonsense	23	4				27
start loss			2			2
frameshift	25	6	2			33
inframe indel			6			6
splice donor/acceptor (+/-2bp)		18	1			19
splice region			23	27	2	52
non coding			37	143	64	244
Total	48	31	500	316	74

Highest pathogenic variant AF is 0.0000920

Variants in TTC21B

This is a list of pathogenic ClinVar variants found in the TTC21B region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-165873530-G-A		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Likely benign (Jan 13, 2018)
2-165873631-T-TA		Jeune thoracic dystrophy • Familial aplasia of the vermis	Uncertain significance (Jun 14, 2016)
2-165873638-T-C		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Uncertain significance (Jan 12, 2018)
2-165873648-T-C		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Uncertain significance (Jan 13, 2018)
2-165873650-C-A		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Benign (Jan 12, 2018)
2-165873651-C-T		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Uncertain significance (Jan 12, 2018)
2-165873668-T-A		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Likely benign (Jan 12, 2018)
2-165873781-G-C		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Benign (Jan 13, 2018)
2-165873829-G-T		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Uncertain significance (Jan 12, 2018)
2-165873845-G-A		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Uncertain significance (Jan 12, 2018)
2-165873877-T-C		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Benign (Jan 12, 2018)
2-165873908-T-G		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Likely benign (Jan 12, 2018)
2-165874025-T-G		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Uncertain significance (Jan 12, 2018)
2-165874074-C-T		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Uncertain significance (Jan 13, 2018)
2-165874075-G-A		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Uncertain significance (Jan 12, 2018)
2-165874099-C-T		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Likely benign (Jan 12, 2018)
2-165874113-G-A		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Uncertain significance (Jan 13, 2018)
2-165874162-C-T		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Uncertain significance (Jan 13, 2018)
2-165874211-T-C		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Uncertain significance (Jan 13, 2018)
2-165874215-A-G		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Uncertain significance (Jan 13, 2018)
2-165874224-T-C		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Benign (Jan 13, 2018)
2-165874238-C-T		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Benign (Jan 13, 2018)
2-165874239-G-A		Asphyxiating thoracic dystrophy 4 • Nephronophthisis 12	Likely benign (Jan 12, 2018)
2-165874282-G-C		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Uncertain significance (Jan 12, 2018)
2-165874295-A-G		Nephronophthisis 12 • Asphyxiating thoracic dystrophy 4	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TTC21B	protein_coding	protein_coding	ENST00000243344	29	96369

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.70e-26	0.880	125534	0	214	125748	0.000851

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.409	724	694	1.04	0.0000365	8634
Missense in Polyphen		187	188.36	0.99278		2389
Synonymous	-0.923	257	239	1.08	0.0000121	2380
Loss of Function	2.64	53	78.2	0.678	0.00000393	988

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000674	0.000674
Ashkenazi Jewish	0.000398	0.000397
East Asian	0.00125	0.00125
Finnish	0.000650	0.000647
European (Non-Finnish)	0.00102	0.00101
Middle Eastern	0.00125	0.00125
South Asian	0.000981	0.000980
Other	0.00116	0.00114

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport. Negatively modulates the SHH signal transduction (By similarity). {ECO:0000250}.
• Disease: DISEASE: Note=Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, nephronophtisis, Senior-Loken syndrome, and Jeune asphyxiating thoracic dystrophy among others. TTC21B is causally associated with diverse ciliopathies. It also acts as a modifier gene across the ciliopathy spectrum, interacting in trans with mutations in other ciliopathy-causing genes and contributing to disease manifestation and severity. {ECO:0000269|PubMed:21258341}.; DISEASE: Nephronophthisis 12 (NPHP12) [MIM:613820]: An autosomal recessive disorder resulting in end-stage renal disease. It is a progressive tubulo-interstitial kidney disorder histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Some patients manifest extra-renal features including retinal, skeletal and central nervous system defects. {ECO:0000269|PubMed:21258341}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short-rib thoracic dysplasia 4 with or without polydactyly (SRTD4) [MIM:613819]: A form of short-rib thoracic dysplasia, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. {ECO:0000269|PubMed:21258341}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 11 (JBTS11) [MIM:613820]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. {ECO:0000269|PubMed:21258341, ECO:0000269|PubMed:22425360}. Note=The disease may be caused by mutations affecting the gene represented in this entry.
• Pathway: Signal Transduction;Hedgehog ,off, state;Signaling by Hedgehog;Intraflagellar transport;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.0989

Intolerance Scores

• loftool: 0.986
• rvis_EVS: 0.62
• rvis_percentile_EVS: 83.26

Haploinsufficiency Scores

• pHI: 0.135
• hipred: N
• hipred_score: 0.418
• ghis: 0.505

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.157

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Ttc21b
• Phenotype: limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); renal/urinary system phenotype; skeleton phenotype; embryo phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: ttc21b
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: shortened

Gene ontology

• Biological process: regulation of transcription by RNA polymerase II;smoothened signaling pathway;regulation of smoothened signaling pathway;ventricular system development;forebrain dorsal/ventral pattern formation;intraciliary retrograde transport;intraciliary transport involved in cilium assembly;protein localization to cilium
• Cellular component: nuclear chromatin;cytoplasm;cytoskeleton;cilium;intraciliary transport particle A;ciliary tip