rs200158932

chr8-67076486-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.73

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004075825).
• 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=3, 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. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSPP1	NM_001382391.1	c.104A>G	p.Lys35Arg	missense_variant	3/31	ENST00000678616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSPP1	ENST00000678616.1	c.104A>G	p.Lys35Arg	missense_variant	3/31		NM_001382391.1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152046 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000951 AC XY: 114 AN XY: 119870

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.: 11 Cov.: 26 AF XY: 0.000826 AC XY: 584 AN XY: 707070

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.: 0 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74400

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.: 0

Bravo AF: 0.000941

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000492 AC: 4

ExAC AF: 0.000911 AC: 110

Asia WGS AF: 0.00202 AC: 7 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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	- -

Joubert syndrome 21 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

CSPP1-related condition Benign:1

Likely benign, criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs200158932; hg19: chr8-67988721;