NM_001382391.1:c.2829-9_2968+11del

Variant names:

• chr8-67172403-CATTTATCTATAGGAAAAAGGAAAGGAATCCCATGGATATATTTGATATGGCTAGACATCGGTTGCAAGCTCCTGTCAGAAGACAGTCCCCTAAGGGCTTAGACGCTGCCACTTTTCAGAATGTTCATGATTTTAATGAGCTGAAAGATAGAGGTGAGTAG-C
• rs1554614893
• NM_001382391.1:c.2829-9_2968+11del

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001382391.1(CSPP1):​c.2829-9_2968+11del variant causes a exon loss, splice acceptor, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CSPP1 NM_001382391.1 exon_loss, splice_acceptor, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.946
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Joubert syndrome 21

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with Jeune asphyxiating thoracic dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 8-67172403-CATTTATCTATAGGAAAAAGGAAAGGAATCCCATGGATATATTTGATATGGCTAGACATCGGTTGCAAGCTCCTGTCAGAAGACAGTCCCCTAAGGGCTTAGACGCTGCCACTTTTCAGAATGTTCATGATTTTAATGAGCTGAAAGATAGAGGTGAGTAG-C is Pathogenic according to our data. Variant chr8-67172403-CATTTATCTATAGGAAAAAGGAAAGGAATCCCATGGATATATTTGATATGGCTAGACATCGGTTGCAAGCTCCTGTCAGAAGACAGTCCCCTAAGGGCTTAGACGCTGCCACTTTTCAGAATGTTCATGATTTTAATGAGCTGAAAGATAGAGGTGAGTAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 434846.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSPP1	NM_001382391.1	c.2829-9_2968+11del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 25 of 31	ENST00000678616.1	NP_001369320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSPP1	ENST00000678616.1	c.2829-9_2968+11del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 25 of 31		NM_001382391.1	ENSP00000504733.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 21 Pathogenic:1

May 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.95
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554614893; hg19: chr8-68084638;