rs766608755
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000552810.6(CEP290):c.1860_1863del(p.Arg621IlefsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000223 in 1,347,476 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: not found (cov: 32)
Exomes 𝑓: 0.0000022 ( 0 hom. )
Consequence
CEP290
ENST00000552810.6 frameshift
ENST00000552810.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.47
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
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-88115143-CTCTT-C is Pathogenic according to our data. Variant chr12-88115143-CTCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 194988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88115143-CTCTT-C is described in Lovd as [Pathogenic]. Variant chr12-88115143-CTCTT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CEP290 | NM_025114.4 | c.1860_1863del | p.Arg621IlefsTer2 | frameshift_variant | 19/54 | ENST00000552810.6 | NP_079390.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CEP290 | ENST00000552810.6 | c.1860_1863del | p.Arg621IlefsTer2 | frameshift_variant | 19/54 | 1 | NM_025114.4 | ENSP00000448012 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000147 AC: 3AN: 204060Hom.: 0 AF XY: 0.0000182 AC XY: 2AN XY: 110122
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GnomAD4 exome AF: 0.00000223 AC: 3AN: 1347476Hom.: 0 AF XY: 0.00000298 AC XY: 2AN XY: 671886
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 07, 2021 | - - |
Leber congenital amaurosis 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PVS1,PM2,PM3 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 28, 2014 | - - |
Bardet-Biedl syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 01, 2024 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 13, 2023 | This sequence change creates a premature translational stop signal (p.Arg621Ilefs*2) 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). This variant is present in population databases (rs766608755, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with CEP290-related conditions (PMID: 17345604, 27894351). This variant is also known as c.1855-1858delAAAG. ClinVar contains an entry for this variant (Variation ID: 194988). For these reasons, this variant has been classified as Pathogenic. - |
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