rs281865192
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_025114.4(CEP290):c.2991+1655A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 151,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00027 ( 0 hom., cov: 29)
Consequence
CEP290
NM_025114.4 intron
NM_025114.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0410
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-88101183-T-C is Pathogenic according to our data. Variant chr12-88101183-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88101183-T-C is described in Lovd as [Pathogenic]. Variant chr12-88101183-T-C is described in Lovd as [Pathogenic]. Variant chr12-88101183-T-C is described in Lovd as [Likely_pathogenic]. Variant chr12-88101183-T-C is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CEP290 | NM_025114.4 | c.2991+1655A>G | intron_variant | ENST00000552810.6 | NP_079390.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CEP290 | ENST00000552810.6 | c.2991+1655A>G | intron_variant | 1 | NM_025114.4 | ENSP00000448012.1 |
Frequencies
GnomAD3 genomes 0.000270 AC: 41AN: 151912Hom.: 0 Cov.: 29
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We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome 0.000270 AC: 41AN: 151912Hom.: 0 Cov.: 29 AF XY: 0.000148 AC XY: 11AN XY: 74202
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:25Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:8Other:1
| not provided, no classification provided | literature only | Retina International | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2023 | Reported as the most common pathogenic variant among individuals of North American and North Western European background (PMID: 16909394, 34196655); Published functional studies demonstrate a damaging effect resulting in the insertion of an aberrant exon into approximately half of CEP290 transcripts and reduced CEP290 mRNA levels in comparison to wild type (PMID: 25761237, 23344081); This variant is associated with the following publications: (PMID: 22842229, 20683928, 20805370, 27106101, 31429209, 23591405, 19823873, 24767827, 17564967, 17345604, 20130272, 23344081, 23343883, 18682808, 20690115, 22355252, 28224992, 24223178, 29186038, 29178642, 30576320, 31087526, 30559420, 31734136, 34327195, 32531858, 32865313, 29398085, 29518907, 33726816, 32037395, 31816670, 28619647, 28510626, 16909394, 25761237, 34196655, 30193310) - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 11, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | CEP290: PM3:Very Strong, PVS1, PP1:Strong, PM2 - |
| 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 | Revvity Omics, Revvity | Dec 22, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Leber congenital amaurosis 10 Pathogenic:4Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Molecular Genetics, University of Zurich | Jan 30, 2021 | - - |
| Pathogenic, no assertion criteria provided | curation | GeneReviews | Mar 29, 2012 | - - |
| Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The CEP290 c.2991+1655A>G 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: PS4, PS3, PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2007 | - - |
CEP290-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 16, 2021 | Variant summary: CEP290 c.2991+1655A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic intronic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and leads to insertion of a cryptic exon encoding a premature stop codon (den Hollander_2006). The variant allele was found at a frequency of 0.00013 in 31310 control chromosomes. c.2991+1655A>G has been reported in the literature in multiple individuals affected with CEP290-Related Disorders, namely Leber Congenital Amaurosis (example, den Hollander_2006). These data indicate that the variant is very likely to be associated with disease. Functional studies have reported ciliary and axonemal defects in patients with this variant (Gerard_2012). Multiple 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 26, 2024 | The CEP290 c.2991+1655A>G variant is predicted to interfere with splicing. This deep intronic variant (also referred to as IVS26+1655A>G) has been reported to create a strong splice-donor site and insert a cryptic exon in the CEP290 transcript (den Hollander et al. 2006. PubMed ID: 16909394). This variant has been reported, in the homozygous or compound heterozygous state along with a second CEP290 variant, in 16 of 76 unrelated patients with autosomal recessive Leber congenital amaurosis (den Hollander et al. 2006. PubMed ID: 16909394). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/1337/). Given the evidence, we interpret c.2991+1655A>G as pathogenic. - |
Retinal dystrophy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 25, 2019 | - - |
Joubert syndrome 5 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Oct 16, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM3,PP3,PP4. - |
Leber congenital amaurosis Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 23, 2017 | - - |
Bardet-Biedl syndrome 14 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Joubert syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
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 | Jan 31, 2024 | This sequence change falls in intron 26 of the CEP290 gene. It does not directly change the encoded amino acid sequence of the CEP290 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs281865192, gnomAD 0.02%). This variant has been observed in individual(s) with Leber congenital amaurosis (PMID: 16909394, 17345604, 17964524). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS26+1655A>G and p.Cys998X. ClinVar contains an entry for this variant (Variation ID: 1337). Studies have shown that this variant results in insertion of 128bp of intronic sequence between exons 26 and 27 and introduces a premature termination codon (PMID: 16909394, 23344081). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Intellectual disability Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 03, 2020 | The variant c.2991+1655A>G, was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was not maternal.The variant likely explains the NDD in this individual. - |
Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 25, 2024 | - - |
Retinitis pigmentosa Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
Computational scores
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BayesDel_noAF
Benign
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Benign
DANN
Benign
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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