rs76567936

Positions:

• chr8-67177708-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001382391.1(CSPP1):​c.3138A>G​(p.Lys1046=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,612,298 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (43 hom.)
• Consequence: CSPP1 NM_001382391.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.73

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]

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 8-67177708-A-G is Benign according to our data. Variant chr8-67177708-A-G is described in ClinVar as [Benign]. Clinvar id is 379767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSPP1	NM_001382391.1	c.3138A>G	p.Lys1046=	synonymous_variant	27/31	ENST00000678616.1	NP_001369320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSPP1	ENST00000678616.1	c.3138A>G	p.Lys1046=	synonymous_variant	27/31		NM_001382391.1	ENSP00000504733

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2298 AN: 152218 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00363 AC: 904 AN: 249370 Hom.: 21 AF XY: 0.00280 AC XY: 379 AN XY: 135294

Gnomad AFR exome AF: 0.0536

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.00141 AC: 2065 AN: 1459962 Hom.: 43 Cov.: 28 AF XY: 0.00123 AC XY: 894 AN XY: 726364

Gnomad4 AFR exome AF: 0.0523

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000814

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0151 AC: 2306 AN: 152336 Hom.: 62 Cov.: 32 AF XY: 0.0140 AC XY: 1046 AN XY: 74494

Gnomad4 AFR AF: 0.0533

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00694 Hom.: 10

Bravo AF: 0.0172

Asia WGS AF: 0.00231 AC: 8 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2016

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. -

Joubert syndrome 21 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	17
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs76567936; hg19: chr8-68089943;