8-67064342-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000262210.11(CSPP1):c.-57C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 1,577,398 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0082 (63 hom.)
• Consequence: CSPP1 ENST00000262210.11 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.393

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 8-67064342-C-T is Benign according to our data. Variant chr8-67064342-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1212697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00685 (1042/152130) while in subpopulation NFE AF= 0.00952 (647/67976). AF 95% confidence interval is 0.00891. There are 10 homozygotes in gnomad4. There are 509 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSPP1	NM_001382391.1			upstream_gene_variant		ENST00000678616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSPP1	ENST00000678616.1			upstream_gene_variant			NM_001382391.1

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152012 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00952

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00824 AC: 11745 AN: 1425268 Hom.: 63 Cov.: 29 AF XY: 0.00803 AC XY: 5679 AN XY: 707438

Gnomad4 AFR exome AF: 0.00115

Gnomad4 AMR exome AF: 0.00325

Gnomad4 ASJ exome AF: 0.000279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00883

Gnomad4 NFE exome AF: 0.00976

Gnomad4 OTH exome AF: 0.00598

GnomAD4 genome AF: 0.00685 AC: 1042 AN: 152130 Hom.: 10 Cov.: 31 AF XY: 0.00684 AC XY: 509 AN XY: 74378

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00550

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.00952

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00680

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CSPP1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	9.2
Dann	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61735315; hg19: chr8-67976577;