8-67159049-AAAGAAAG-AAAGAAAGAAGAAAG

Variant names:

• chr8-67159049-A-AAAGAAAG
• rs863225191
• NM_001382391.1:c.2463_2469dupAGAAGAA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001382391.1(CSPP1):​c.2463_2469dupAGAAGAA​(p.Glu824ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSPP1 NM_001382391.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.52
• Publications: 1 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 12 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 8-67159049-A-AAAGAAAG is Pathogenic according to our data. Variant chr8-67159049-A-AAAGAAAG is described in ClinVar as Pathogenic. ClinVar VariationId is 217643.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382391.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	NM_001382391.1	MANE Select	c.2463_2469dupAGAAGAA	p.Glu824ArgfsTer7	frameshift	Exon 21 of 31	NP_001369320.1
	CSPP1	NM_001364869.1		c.2529_2535dupAGAAGAA	p.Glu846ArgfsTer7	frameshift	Exon 20 of 30	NP_001351798.1
	CSPP1	NM_024790.7		c.2448_2454dupAGAAGAA	p.Glu819ArgfsTer7	frameshift	Exon 19 of 29	NP_079066.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.2463_2469dupAGAAGAA	p.Glu824ArgfsTer7	frameshift	Exon 21 of 31	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.2529_2535dupAGAAGAA	p.Glu846ArgfsTer7	frameshift	Exon 20 of 30	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.1413_1419dupAGAAGAA	p.Glu474ArgfsTer7	frameshift	Exon 16 of 26	ENSP00000430092.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome 21 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
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: rs863225191; hg19: chr8-68071284;