rs386834158
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025114.4(CEP290):c.5493del(p.Ala1832ProfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,563,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
CEP290
NM_025114.4 frameshift
NM_025114.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.39
Genes affected
CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 12-88077789-CT-C is Pathogenic according to our data. Variant chr12-88077789-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 56739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88077789-CT-C is described in Lovd as [Pathogenic]. Variant chr12-88077789-CT-C is described in Lovd as [Likely_pathogenic]. Variant chr12-88077789-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CEP290 | NM_025114.4 | c.5493del | p.Ala1832ProfsTer19 | frameshift_variant | 40/54 | ENST00000552810.6 | |
LOC124902977 | XR_007063393.1 | n.887-4519del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP290 | ENST00000552810.6 | c.5493del | p.Ala1832ProfsTer19 | frameshift_variant | 40/54 | 1 | NM_025114.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151748Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000224 AC: 5AN: 223598Hom.: 0 AF XY: 0.0000247 AC XY: 3AN XY: 121346
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GnomAD4 exome AF: 0.0000149 AC: 21AN: 1412148Hom.: 0 Cov.: 27 AF XY: 0.0000128 AC XY: 9AN XY: 702784
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | CEP290: PVS1, PM2, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 12, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2019 | The c.5493delA pathogenic variant in the CEP290 gene has been reported previously in association with CEP290-related disorders (Tallila et al., 2009; Travaglini et al., 2009; Cideciyan et al., 2011). The deletion causes a frameshift starting with codon Alanine 1832, changes this amino acid to a Proline residue and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Ala1832ProfsX19. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.5493delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). - |
Meckel syndrome, type 4 Pathogenic:3
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2020 | Variant summary: CEP290 c.5493delA (p.Ala1832ProfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.2e-05 in 223598 control chromosomes. c.5493delA has been reported in the literature in individuals affected with Joubert syndromerelated disorders, retinal dystrophy, or Leber congenital amaurosis (Brancati_2007, Carss_2017, Feldhaus_2020). These data indicate that the variant may be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Joubert syndrome 5 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jul 09, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 08, 2021 | This variant was identified as compound heterozygous with NM_025114.4:c.2279_2280del. - |
CEP290-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 13, 2022 | - - |
Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Leber congenital amaurosis 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The CEP290 c.5493del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP1, PVS1. Based on this evidence we have classified this variant as Pathogenic. - |
Polycystic kidney disease;C0266292:Abnormality of the kidney;C0431399:Familial aplasia of the vermis;C1840379:Cerebellar vermis hypoplasia;C1847762:Cerebellar cyst;C3275899:Hyperechogenic kidneys Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 29, 2014 | - - |
Bardet-Biedl syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 29, 2024 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Ala1832Profs*19) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Leber congenital amaurosis and/or Meckel-Gruber syndrome (PMID: 17705300, 20683928, 21245082). This variant is also known as 5489_5493delA, c.5489del and p.Gln1830fs. ClinVar contains an entry for this variant (Variation ID: 56739). For these reasons, this variant has been classified as Pathogenic. - |
Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Oct 08, 2021 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at