rs200161440

Variant names:

• chr8-67195405-C-T
• rs200161440
• NM_001382391.1:c.3493C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001382391.1(CSPP1):​c.3493C>T​(p.Pro1165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,613,936 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1165R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (7 hom.)
• Consequence: CSPP1 NM_001382391.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.28
• Publications: 5 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]

ARFGEF1 (HGNC:15772): (ADP ribosylation factor guanine nucleotide exchange factor 1) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Aug 2011]

ARFGEF1 Gene-Disease associations (from GenCC):

• developmental delay, impaired speech, and behavioral abnormalities, with or without seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047197044).
• BP6: Variant 8-67195405-C-T is Benign according to our data. Variant chr8-67195405-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00131 (199/152268) while in subpopulation AMR AF = 0.00432 (66/15288). AF 95% confidence interval is 0.00348. There are 1 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.3493C>T	p.Pro1165Ser	missense	Exon 31 of 31	NP_001369320.1
	CSPP1	NM_001364869.1		c.3559C>T	p.Pro1187Ser	missense	Exon 30 of 30	NP_001351798.1
	CSPP1	NM_024790.7		c.3478C>T	p.Pro1160Ser	missense	Exon 29 of 29	NP_079066.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.3493C>T	p.Pro1165Ser	missense	Exon 31 of 31	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.3559C>T	p.Pro1187Ser	missense	Exon 30 of 30	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.2443C>T	p.Pro815Ser	missense	Exon 26 of 26	ENSP00000430092.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00134 AC: 335 AN: 249478 AF XY: 0.00119

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000698

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.000861 AC: 1259 AN: 1461668 Hom.: 7 Cov.: 31 AF XY: 0.000916 AC XY: 666 AN XY: 727160

African (AFR) AF: 0.00111 AC: 37 AN: 33476

American (AMR) AF: 0.00230 AC: 103 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 361 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.0164 AC: 94 AN: 5730

European-Non Finnish (NFE) AF: 0.000445 AC: 495 AN: 1111848

Other (OTH) AF: 0.00237 AC: 143 AN: 60386

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74456

African (AFR) AF: 0.000289 AC: 12 AN: 41544

American (AMR) AF: 0.00432 AC: 66 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00146 Hom.: 3

Bravo AF: 0.00147

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00118 AC: 10

ExAC AF: 0.00102 AC: 124

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSPP1: BP4

Jun 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25616960, 26092869)

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

CSPP1-related disorder Benign:1

Aug 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.043
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.047
Sift	Benign	0.15	T
Sift4G	Benign	0.49	T
Polyphen		0.49	P
Vest4		0.21
MVP		0.47
MPC		0.37
ClinPred		0.028	T
GERP RS		4.6
gMVP		0.068
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200161440; hg19: chr8-68107640;