8-67064428-A-G

Position:

chr8-67064428-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000262210.11(CSPP1):c.30A>G(p.Val10=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00693 in 1,613,876 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V10V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0046 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0072 ( 41 hom. )

Consequence

CSPP1
ENST00000262210.11 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.05

Variant links:

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 links:

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]

COPS5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-67064428-A-G is Benign according to our data. Variant chr8-67064428-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 379431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00461 (702/152248) while in subpopulation NFE AF= 0.00804 (547/68002). AF 95% confidence interval is 0.00749. There are 5 homozygotes in gnomad4. There are 305 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSPP1	NM_001382391.1 linkuse as main transcript	c.-121A>G		5_prime_UTR_variant	1/31	ENST00000678616.1	NP_001369320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSPP1	ENST00000678616.1 linkuse as main transcript	c.-121A>G		5_prime_UTR_variant	1/31		NM_001382391.1	ENSP00000504733

Frequencies

GnomAD3 genomes

AF:

0.00462

AC:

703

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00806

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00466

AC:

1159

AN:

248848

Hom.:

AF XY:

0.00443

AC XY:

598

AN XY:

135114

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000981

Gnomad FIN exome

AF:

0.00196

Gnomad NFE exome

AF:

0.00772

Gnomad OTH exome

AF:

0.00529

GnomAD4 exome

AF:

0.00717

AC:

10480

AN:

1461628

Hom.:

Cov.:

AF XY:

0.00699

AC XY:

5085

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.0123

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.00219

Gnomad4 NFE exome

AF:

0.00851

Gnomad4 OTH exome

AF:

0.00628

GnomAD4 genome

AF:

0.00461

AC:

702

AN:

152248

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

305

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00804

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00730

Hom.:

Bravo

AF:

0.00465

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, not in splice consensus -

CSPP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Joubert syndrome 21

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

CSPP1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.2

DANN

Benign

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over