rs1060499781
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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.6818+1_6818+2insGG variant causes a splice donor change. The variant allele was found at a frequency of 0.00000274 in 1,460,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CEP290
NM_025114.4 splice_donor
NM_025114.4 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.97
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
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.4, offset of 2, new splice context is: gggGTagga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-88058846-A-ACC is Pathogenic according to our data. Variant chr12-88058846-A-ACC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CEP290 | NM_025114.4 | c.6818+1_6818+2insGG | splice_donor_variant | ENST00000552810.6 | |||
LOC124902977 | XR_007063393.1 | n.886+1827_886+1828dup | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP290 | ENST00000552810.6 | c.6818+1_6818+2insGG | splice_donor_variant | 1 | NM_025114.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460904Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726670
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 14 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2023 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | This sequence change affects a splice site in intron 49 of the CEP290 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 402224). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Joubert syndrome 5 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 30, 2016 | The c.6818+1_6818+2insGG splice variant in the CEP290 gene has not been previously reported in published literature and is absent from the population databases (ESP; 1000 Genomes; ExAC). Splice-site, nonsense, and frameshift variants have been described in the CEP290 gene in several affected individuals (including nonsense and frameshift variants downstream of this splice variant) and thus, loss of function is a known mechanism of disease. In silico splicing algorithms predict this variant will cause altered splicing (Human Splice Finder = Broken WT Donor Site, New Donor Site). Therefore, this collective evidence supports the classification of the c.6818+1_6818+2insGG as a Likely Pathogenic variant for Joubert Syndrome and Related Disorders. Because this gene is expressed in blood cells, RNA-splicing studies can be performed to validate this classification (see recommendation). - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at