CSPP1

protein-coding

centrosome and spindle pole associated protein 1

Gene summary

This gene encodes a centrosome and spindle pole associated protein. The encoded protein plays a role in cell-cycle progression and spindle organization, regulates cytokinesis, interacts with Nephrocystin 8 and is required for cilia formation. Mutations in this gene result in primary cilia abnormalities and classical Joubert syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

MANE transcript

NM_001382391.1

Inheritance

ClinVar variants

P:143U:544B:264

Top phenotype

Joubert syndrome 21

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr8:67,062,417-67,196,778

External References & Databases

Ensembl (ENSG00000104218)

Transcript & Mutation Effects

hg38 • Region Span ~134.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome 21DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014288

Submitter: G2P

Meckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Joubert syndrome 21STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014288

Submitter: Labcorp Genetics (formerly Invitae)

Joubert syndrome with Jeune asphyxiating thoracic dystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018342

Submitter: Orphanet

Joubert syndrome 21DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014288

Submitter: ClinGen

CSPP1 was first reported in relation to autosomal-recessive classical Joubert Syndrome (JBTS) with or without Jeune asphyxiating thoracic dystrophy (JATD) in 28 individuals, and with a Meckel Syndrome (MKS)-like phenotype in 2 individuals from a single family, in three back-to-back publications in 2014 (Akizu et al., PMID:24360807; Tuz et al., PMID:24360808; Shaheen et al., PMID: 24360803). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms AND/OR inheritance pattern AND/OR phenotypic variability. Therefore, the three disease entities have been lumped into one disease entity, Joubert Syndrome 21 (OMIM:615636). There are 31 null variants (variant types: 9 nonsense, 6 splice site, 16 frameshift) that have been reported in >30 probands in at least 7 publications (PMIDs 24360807, 24360808, 24360803, 32386258, 26092869, 27434533, 31980526) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be biallelic loss of function. This gene-disease association is also supported by experimental evidence e.g. zebrafish-morpholino, expression studies, and in vitro functional assays with primary patient cells (dermal fibroblasts) (PMIDs 24360807, 24360808, 24360803). Renal involvement in terms of hyperechogenic (oligocystic) kidneys was reported infrequently in a minority of patients (about 3/30). In summary, CSPP1 is definitively associated with a spectrum of autosomal-recessive ciliopathy phenotypes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy GCEP on the meeting date 6/23/2021 (SOP Version 8).

Clinical Genomic Database (CGD)

Joubert syndrome 21AR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: General

Rationale: 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

Comments: Mild sensorineural hearing loss has been described in several individuals

Refs: 24360803; 24360807; 24360808

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CSPP1 variants in ClinVar

10 Conditions Cataloged

Joubert syndrome 21Total: 1048

not providedTotal: 218

Inborn genetic diseasesTotal: 175

not specifiedTotal: 124

CSPP1-related disorderTotal: 81

Retinal dystrophyTotal: 9

Dandy-Walker malformationTotal: 1

Meckel-Gruber syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001382391.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	227 clinvar	2 clinvar	234
missense		1 clinvar	516 clinvar	32 clinvar	1 clinvar	550
nonsense	22 clinvar	17 clinvar	5 clinvar			44
start loss						0
frameshift	42 clinvar	30 clinvar	10 clinvar			82
splice donor/acceptor (+/-2bp)	9 clinvar	22 clinvar	8 clinvar	2 clinvar		41
Total	73	70	544	261	3	951

Highest pathogenic variant AF is 0.00012919896

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 129 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001382391.1	RefSeq	NP_001369320.1	30	MANE Select
ENST00000678616.1	Ensembl	ENSP00000504733.1	30	MANE Select
NM_001291339.2	RefSeq	NP_001278268.1	23	Standard
NM_001363131.2	RefSeq	NP_001350060.1	29	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cspp1a	Danio rerio	Structure: pronephros Quality: cystic abnormal

Gene / Model

Organism

Observed Phenotype

cspp1a

Danio rerio

Structure: pronephros

Quality: cystic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of cytokinesis
positive regulation of cell division

Cellular Component

spindle pole
cytoplasm
centrosome
spindle
microtubule

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262210
Coding exons: 29
Length: 133838
Individuals with no LoFs: 124581
Homozygous LoFs: 0
Heterozygous LoFs: 220
Defined: 124801
p: 0.000882

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.654	601	648	0.928	0.0000342	8060
Missense (PolyPhen)		171	206.79	0.82694		2662
Synonymous	-0.0213	218	218	1.00	0.0000109	2204
Loss of Function	2.04	55	73.9	0.744	0.00000430	878

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00066	0.00065	rare
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0022	0.0021	notable
Finnish	0.00019	0.00019	rare
European (Non-Finnish)	0.00088	0.00087	rare
South Asian	0.0011	0.0010	notable
Other	0.00066	0.00066	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in cell-cycle-dependent microtubule organization. {ECO:0000269|PubMed:16826565}.;
Disease: DISEASE: Joubert syndrome 21 (JBTS21) [MIM:615636]: 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, renal disease, liver fibrosis, and polydactyly. {ECO:0000269|PubMed:24360803, ECO:0000269|PubMed:24360807, ECO:0000269|PubMed:24360808}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.953
RVIS EVS: -0.26
RVIS percentile EVS: 34.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.204

Gene Damage Prediction

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