rs587777139

Positions:

• chr8-67158462-CAA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001382391.1(CSPP1):​c.2259_2260delAA​(p.Glu755fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000926 in 1,597,440 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: CSPP1 NM_001382391.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.963

Genes affected

CSPP1 (HGNC:26193): (centrosome and spindle pole associated protein 1) 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]

CSPP1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-67158462-CAA-C is Pathogenic according to our data. Variant chr8-67158462-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 100667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-67158462-CAA-C is described in Lovd as [Pathogenic]. Variant chr8-67158462-CAA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSPP1	NM_001382391.1	c.2259_2260delAA	p.Glu755fs	frameshift_variant	20/31	ENST00000678616.1	NP_001369320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSPP1	ENST00000678616.1	c.2259_2260delAA	p.Glu755fs	frameshift_variant	20/31		NM_001382391.1	ENSP00000504733.1

Frequencies

GnomAD3 genomes AF: 0.0000924 AC: 14 AN: 151594 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000923 AC: 22 AN: 238258 Hom.: 0 AF XY: 0.0000928 AC XY: 12 AN XY: 129316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000310

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000235

Gnomad SAS exome AF: 0.0000716

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000927 AC: 134 AN: 1445846 Hom.: 0 AF XY: 0.0000974 AC XY: 70 AN XY: 718824

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.0000473

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.000109

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.0000977

Gnomad4 OTH exome AF: 0.0000671

GnomAD4 genome AF: 0.0000924 AC: 14 AN: 151594 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73974

Gnomad4 AFR AF: 0.000146

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000110

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 21 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 24, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2023	Variant summary: CSPP1 c.2244_2245delAA (p.Glu750GlyfsX30) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 9.2e-05 in 238258 control chromosomes. c.2244_2245delAA has been reported in the literature in individuals affected with ciliopathies such as Joubert Syndrome and Meckel-Gruber-like syndrome ((example, Tuz_2014, Fleming_2017). The following publications have been ascertained in the context of this evaluation (PMID: 29146704, 24360808). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 11, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2244_2245delAA (p.E750Gfs*30) variant has been previously reported as disease causing in individuals with Joubert syndrome [PMID 24360807, 27894351, 24360808] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 02, 2014	- -
Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 2023	This sequence change creates a premature translational stop signal (p.Glu750Glyfs*30) in the CSPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CSPP1 are known to be pathogenic (PMID: 24360807, 24360808). This variant is present in population databases (rs751779946, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Joubert syndrome and Meckel syndrome (PMID: 24360807, 24360808, 27894351). ClinVar contains an entry for this variant (Variation ID: 100667). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 22, 2021	PVS1, PM2, PM3 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 25, 2024

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24360807, 24360808, 26092869, 27894351, 35183220, 31964843) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587777139; hg19: chr8-68070697;