chr12-88086038-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_025114.4(CEP290):c.4437+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000133 in 1,606,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000086 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
CEP290
NM_025114.4 splice_donor
NM_025114.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.94
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 16 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.018010752 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of 40, new splice context is: ttgGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 12-88086038-C-T is Pathogenic according to our data. Variant chr12-88086038-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 285948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88086038-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CEP290 | NM_025114.4 | c.4437+1G>A | splice_donor_variant | ENST00000552810.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP290 | ENST00000552810.6 | c.4437+1G>A | splice_donor_variant | 1 | NM_025114.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152030Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000542 AC: 13AN: 239944Hom.: 0 AF XY: 0.0000385 AC XY: 5AN XY: 129856
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GnomAD4 exome AF: 0.000138 AC: 200AN: 1454192Hom.: 0 Cov.: 30 AF XY: 0.000125 AC XY: 90AN XY: 722436
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GnomAD4 genome AF: 0.0000855 AC: 13AN: 152030Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74282
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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:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 20, 2021 | DNA sequence analysis of the CEP290 gene demonstrated a sequence change in the canonical splice donor site of intron 34, c.4437+1G>A. This sequence change is predicted to disrupt the canonical splice donor site, and affect normal splicing of exon 34. This c.4437+1G>A change does not appear to have been previously described in individuals with CEP290-related disorders. This sequence change has been described in the gnomAD database in the non-Finnish European subpopulation with a low frequency of 0.013% (dbSNP rs760915898). Collectively, this evidence suggests c.4437+1G>A is likely pathogenic, however, functional studies have not been performed to prove this conclusively. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 09, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2023 | Reported in a patient with developmental delay, infantile spasms, renal cysts and nephronophthisis (Thiffault et al., 2018); however, this patient also had a variant in a candidate gene that may be related to the phenotype; Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30267408, 31964843, 30311385) - |
CEP290-related disorder Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 30, 2024 | The CEP290 c.4437+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been observed in a large dataset of worldwide populations used to evaluate the frequency or percentage of individuals carrying a disease-causing variant in genes associated with autosomal recessive inherited retinal diseases (IRDs) (Table S3, Hanany et al. 2020. PubMed ID: 31964843). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in CEP290 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The CEP290 c.4437+1G>A (p.?) variant is predicted to disrupt a canonical splice donor site, which may result in an aberrant protein. This variant has not been reported in association with CEP290-related disorders. - |
Leber congenital amaurosis Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change affects a donor splice site in intron 34 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 present in population databases (rs760915898, gnomAD 0.01%). 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: 285948). 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. - |
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
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
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
Pathogenic
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
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DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at