rs370119681
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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):โc.5182G>Tโ(p.Glu1728Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000013 in 1,612,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (โ โ ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: ๐ 0.000033 ( 0 hom., cov: 32)
Exomes ๐: 0.000011 ( 0 hom. )
Consequence
CEP290
NM_025114.4 stop_gained
NM_025114.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.31
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 12-88080226-C-A is Pathogenic according to our data. Variant chr12-88080226-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88080226-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CEP290 | NM_025114.4 | c.5182G>T | p.Glu1728Ter | stop_gained | 38/54 | ENST00000552810.6 | |
LOC124902977 | XR_007063393.1 | n.887-2087C>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP290 | ENST00000552810.6 | c.5182G>T | p.Glu1728Ter | stop_gained | 38/54 | 1 | NM_025114.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152092Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000162 AC: 4AN: 246988Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 134084
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23559409, 21866095, 25525159, 28559085, 24868008, 21068128) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Dec 06, 2022 | PVS1, PM2_SUP, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 14, 2014 | - - |
Leber congenital amaurosis 10 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen | Mar 17, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The CEP290 c.5182G>T 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: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. - |
Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 19, 2020 | - - |
Bardet-Biedl syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2024 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | This premature translational stop signal has been observed in individual(s) with Joubert syndrome, or severe early childhood onset retinal dystrophy (PMID: 21068128, 28559085). 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 sequence change creates a premature translational stop signal (p.Glu1728*) 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). ClinVar contains an entry for this variant (Variation ID: 197044). For these reasons, this variant has been classified as Pathogenic. - |
Meckel syndrome, type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 08, 2022 | Variant summary: CEP290 c.5182G>T (p.Glu1728X) 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 1.6e-05 in 247180 control chromosomes (gnomAD and publication data). c.5182G>T has been reported in the literature in individuals affected with Joubert syndrome (Otto_2011, Chaki_2011, Summers_2017, Fleming_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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