rs371525247
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025114.4(CEP290):c.5932C>T(p.Arg1978Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000151 in 1,458,392 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
CEP290
NM_025114.4 stop_gained
NM_025114.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.63
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 12-88071373-G-A is Pathogenic according to our data. Variant chr12-88071373-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88071373-G-A is described in Lovd as [Pathogenic]. Variant chr12-88071373-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CEP290 | NM_025114.4 | c.5932C>T | p.Arg1978Ter | stop_gained | 43/54 | ENST00000552810.6 | |
LOC124902977 | XR_007063393.1 | n.887-10940G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP290 | ENST00000552810.6 | c.5932C>T | p.Arg1978Ter | stop_gained | 43/54 | 1 | NM_025114.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247480Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134234
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1458392Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 725558
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 18, 2017 | - - |
Bardet-Biedl syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 15, 2023 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg1978*) 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 (rs371525247, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with features of CEP290-related disease (PMID: 17617513, 26092869). ClinVar contains an entry for this variant (Variation ID: 217637). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Joubert syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
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
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