rs761197192
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_014679.5(CEP57):βc.1297_1305delβ(p.Gln433_Lys435del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000013 in 1,611,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.000014 ( 0 hom. )
Consequence
CEP57
NM_014679.5 inframe_deletion
NM_014679.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.89
Genes affected
CEP57 (HGNC:30794): (centrosomal protein 57) This gene encodes a cytoplasmic protein called Translokin. This protein localizes to the centrosome and has a function in microtubular stabilization. The N-terminal half of this protein is required for its centrosome localization and for its multimerization, and the C-terminal half is required for nucleating, bundling and anchoring microtubules to the centrosomes. This protein specifically interacts with fibroblast growth factor 2 (FGF2), sorting nexin 6, Ran-binding protein M and the kinesins KIF3A and KIF3B, and thus mediates the nuclear translocation and mitogenic activity of the FGF2. It also interacts with cyclin D1 and controls nucleocytoplasmic distribution of the cyclin D1 in quiescent cells. This protein is crucial for maintaining correct chromosomal number during cell division. Mutations in this gene cause mosaic variegated aneuploidy syndrome, a rare autosomal recessive disorder. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]
MTMR2 (HGNC:7450): (myotubularin related protein 2) This gene is a member of the myotubularin family of phosphoinositide lipid phosphatases. The encoded protein possesses phosphatase activity towards phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4B, an autosomal recessive demyelinating neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_014679.5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CEP57 | NM_014679.5 | c.1297_1305del | p.Gln433_Lys435del | inframe_deletion | 11/11 | ENST00000325542.10 | NP_055494.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CEP57 | ENST00000325542.10 | c.1297_1305del | p.Gln433_Lys435del | inframe_deletion | 11/11 | 1 | NM_014679.5 | ENSP00000317902 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250912Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135728
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1459792Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 726276
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GnomAD4 genome 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74420
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mosaic variegated aneuploidy syndrome 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 11, 2020 | In summary, this is a rare in-frame deletion with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant is present in population databases (rs761197192, ExAC 0.03%) but has not been reported in the literature in individuals with a CEP57-related disease. This sequence change deletes 9 nucleotides from exon 11 of the CEP57 mRNA (c.1297_1305delCAGAAGAAG). This leads to the deletion of 3 amino acid residues in the CEP57 protein (p.Gln433_Lys435del) but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at