rs114177619

chr8-67149784-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001382391.1(CSPP1):c.1977T>C(p.Thr659=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,534,256 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (12 hom.)
• Consequence: CSPP1 NM_001382391.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.001318
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.16

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 8-67149784-T-C is Benign according to our data. Variant chr8-67149784-T-C is described in ClinVar as [Benign]. Clinvar id is 474852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-67149784-T-C is described in Lovd as [Likely_benign]. Variant chr8-67149784-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00776 (1182/152232) while in subpopulation AFR AF= 0.0271 (1127/41542). AF 95% confidence interval is 0.0258. There are 13 homozygotes in gnomad4. There are 553 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSPP1	NM_001382391.1	c.1977T>C	p.Thr659=	splice_region_variant, synonymous_variant	18/31	ENST00000678616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSPP1	ENST00000678616.1	c.1977T>C	p.Thr659=	splice_region_variant, synonymous_variant	18/31		NM_001382391.1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1178 AN: 152114 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00189 AC: 375 AN: 198118 Hom.: 7 AF XY: 0.00150 AC XY: 164 AN XY: 109114

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000205

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000660 AC: 912 AN: 1382024 Hom.: 12 Cov.: 30 AF XY: 0.000611 AC XY: 419 AN XY: 685634

Gnomad4 AFR exome AF: 0.0271

Gnomad4 AMR exome AF: 0.000913

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000270

Gnomad4 SAS exome AF: 0.0000281

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00776 AC: 1182 AN: 152232 Hom.: 13 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74436

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00844

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Joubert syndrome 21 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	14
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.080
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs114177619; hg19: chr8-68062019;