rs200158932

Positions:

chr8-67076486-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001382391.1(CSPP1):c.104A>G(p.Lys35Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000751 in 1,571,978 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 11 hom. )

Consequence

CSPP1
NM_001382391.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.73

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 -9 ACMG points.

BP6

Variant 8-67076486-A-G is Benign according to our data. Variant chr8-67076486-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446051.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000808 (123/152164) while in subpopulation SAS AF= 0.00332 (16/4816). AF 95% confidence interval is 0.00208. There are 0 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSPP1	NM_001382391.1 linkuse as main transcript	c.104A>G	p.Lys35Arg	missense_variant	3/31	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.104A>G	p.Lys35Arg	missense_variant	3/31		NM_001382391.1	ENSP00000504733

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000874

AC:

192

AN:

219582

Hom.:

AF XY:

0.000951

AC XY:

114

AN XY:

119870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000640

Gnomad ASJ exome

AF:

0.00442

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00314

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000509

Gnomad OTH exome

AF:

0.00136

GnomAD4 exome

AF:

0.000744

AC:

1057

AN:

1419814

Hom.:

Cov.:

AF XY:

0.000826

AC XY:

584

AN XY:

707070

show subpopulations

Gnomad4 AFR exome

AF:

0.0000322

Gnomad4 AMR exome

AF:

0.000859

Gnomad4 ASJ exome

AF:

0.00482

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00372

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000480

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152164

Hom.:

Cov.:

AF XY:

0.000874

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000918

Hom.:

Bravo

AF:

0.000941

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000492

AC:

ExAC

AF:

0.000911

AC:

110

Asia WGS

AF:

0.00202

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 09, 2017	- -

CSPP1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2020

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.2

.;M

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.081

Sift

Benign

0.17

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.68

.;P

Vest4

0.29

MVP

0.62

MPC

0.26

ClinPred

0.044

GERP RS

3.1

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.32

Position offset: 1

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