rs766435188

Positions:

• chr3-134551923-CAGG-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_Moderate PM2 BS1_Supporting

The NM_001353108.3(CEP63):​c.1381_1383del​(p.Glu461del) variant causes a splice acceptor, coding sequence change. The variant allele was found at a frequency of 0.0000638 in 1,597,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: CEP63 NM_001353108.3 splice_acceptor, coding_sequence
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.30

Genes affected

CEP63 (HGNC:25815): (centrosomal protein 63) This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. Several alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.040719695 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: ttctgttttccccttttcAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000357 (54/151442) while in subpopulation AFR AF= 0.00116 (48/41350). AF 95% confidence interval is 0.000899. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP63	NM_001353108.3	c.1381_1383del	p.Glu461del	splice_acceptor_variant, coding_sequence_variant	12/15	ENST00000675561.1	NP_001340037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP63	ENST00000675561.1	c.1381_1383del	p.Glu461del	splice_acceptor_variant, coding_sequence_variant	12/15		NM_001353108.3	ENSP00000502085	A1

Frequencies

GnomAD3 genomes AF: 0.000357 AC: 54 AN: 151338 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000966 AC: 24 AN: 248412 Hom.: 0 AF XY: 0.0000670 AC XY: 9 AN XY: 134348

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.0000883

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: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000332 AC: 48 AN: 1446352 Hom.: 0 AF XY: 0.0000222 AC XY: 16 AN XY: 720148

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.0000906

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000357 AC: 54 AN: 151442 Hom.: 0 Cov.: 31 AF XY: 0.000432 AC XY: 32 AN XY: 73994

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000366

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 23, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This variant, c.1381_1383del, results in the deletion of 1 amino acid(s) of the CEP63 protein (p.Glu461del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766435188, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CEP63-related conditions. ClinVar contains an entry for this variant (Variation ID: 434754). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: 6
DS_AL_spliceai		1.0		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs766435188; hg19: chr3-134270765;