NM_001382391.1:c.104A>G

Variant names:

• chr8-67076486-A-G
• rs200158932
• NM_001382391.1:c.104A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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:4
• Conservation: PhyloP100: 3.73
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 446051.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382391.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	NM_001382391.1	MANE Select	c.104A>G	p.Lys35Arg	missense	Exon 3 of 31	NP_001369320.1
	CSPP1	NM_001364869.1		c.212A>G	p.Lys71Arg	missense	Exon 3 of 30	NP_001351798.1
	CSPP1	NM_024790.7		c.212A>G	p.Lys71Arg	missense	Exon 3 of 29	NP_079066.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.104A>G	p.Lys35Arg	missense	Exon 3 of 31	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.212A>G	p.Lys71Arg	missense	Exon 3 of 30	ENSP00000262210.6
	CSPP1	ENST00000676605.1		c.335A>G	p.Lys112Arg	missense	Exon 4 of 30	ENSP00000503605.1

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

GnomAD2 exomes AF: 0.000874 AC: 192 AN: 219582 AF XY: 0.000951

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 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

African (AFR) AF: 0.0000322 AC: 1 AN: 31028

American (AMR) AF: 0.000859 AC: 31 AN: 36078

Ashkenazi Jewish (ASJ) AF: 0.00482 AC: 119 AN: 24682

East Asian (EAS) AF: 0.00 AC: 0 AN: 38676

South Asian (SAS) AF: 0.00372 AC: 297 AN: 79886

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52608

Middle Eastern (MID) AF: 0.00197 AC: 11 AN: 5576

European-Non Finnish (NFE) AF: 0.000480 AC: 524 AN: 1092636

Other (OTH) AF: 0.00124 AC: 73 AN: 58644

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74400

African (AFR) AF: 0.0000963 AC: 4 AN: 41516

American (AMR) AF: 0.00222 AC: 34 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000919 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:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSPP1: BS1

Mar 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 24, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSPP1-related disorder Benign:1

Aug 19, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
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
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.081
Sift	Benign	0.17	T
Sift4G	Benign	0.40	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
Mutation Taster		=294/6	polymorphism

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

Other links and lift over

dbSNP: rs200158932; hg19: chr8-67988721;