rs370003497

Positions:

• chr8-67074303-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_001382391.1(CSPP1):​c.51C>T​(p.Ala17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,608,422 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: CSPP1 NM_001382391.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.103

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]

COPS5 (HGNC:2240): (COP9 signalosome subunit 5) The protein encoded by this gene is one of the eight subunits of COP9 signalosome, a highly conserved protein complex that functions as an important regulator in multiple signaling pathways. The structure and function of COP9 signalosome is similar to that of the 19S regulatory particle of 26S proteasome. COP9 signalosome has been shown to interact with SCF-type E3 ubiquitin ligases and act as a positive regulator of E3 ubiquitin ligases. This protein is reported to be involved in the degradation of cyclin-dependent kinase inhibitor CDKN1B/p27Kip1. It is also known to be an coactivator that increases the specificity of JUN/AP1 transcription factors. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 8-67074303-C-T is Benign according to our data. Variant chr8-67074303-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 386180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-67074303-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.103 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSPP1	NM_001382391.1	c.51C>T	p.Ala17=	synonymous_variant	2/31	ENST00000678616.1	NP_001369320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSPP1	ENST00000678616.1	c.51C>T	p.Ala17=	synonymous_variant	2/31		NM_001382391.1	ENSP00000504733

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 151768 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000284 AC: 70 AN: 246290 Hom.: 0 AF XY: 0.000239 AC XY: 32 AN XY: 133658

Gnomad AFR exome AF: 0.000261

Gnomad AMR exome AF: 0.0000888

Gnomad ASJ exome AF: 0.000600

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000491

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000430 AC: 626 AN: 1456654 Hom.: 0 Cov.: 29 AF XY: 0.000436 AC XY: 316 AN XY: 724638

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.000158

Gnomad4 ASJ exome AF: 0.000577

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000520

Gnomad4 OTH exome AF: 0.000366

GnomAD4 genome AF: 0.000382 AC: 58 AN: 151768 Hom.: 1 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74078

Gnomad4 AFR AF: 0.0000969

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000434

EpiCase AF: 0.000385

EpiControl AF: 0.000420

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2016	- -

Joubert syndrome 21 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

CSPP1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.2
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs370003497; hg19: chr8-67986538;