chr12-88109070-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_025114.4(CEP290):āc.2479C>Gā(p.Leu827Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000617 in 1,199,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00031 ( 0 hom., cov: 32)
Exomes š: 0.000026 ( 0 hom. )
Consequence
CEP290
NM_025114.4 missense
NM_025114.4 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 2.67
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
In a coiled_coil_region (size 234) in uniprot entity CE290_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_025114.4
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000309 AC: 47AN: 151960Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000108 AC: 15AN: 138948Hom.: 0 AF XY: 0.000104 AC XY: 8AN XY: 76790
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GnomAD4 exome AF: 0.0000258 AC: 27AN: 1047676Hom.: 0 Cov.: 13 AF XY: 0.0000264 AC XY: 14AN XY: 529888
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GnomAD4 genome 0.000309 AC: 47AN: 151960Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74206
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 09, 2024 | The c.2479C>G (p.L827V) alteration is located in exon 23 (coding exon 22) of the CEP290 gene. This alteration results from a C to G substitution at nucleotide position 2479, causing the leucine (L) at amino acid position 827 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Senior-Loken syndrome 6 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
CEP290-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 21, 2024 | The CEP290 c.2479C>G variant is predicted to result in the amino acid substitution p.Leu827Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD, which is likely too common to be a disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Leber congenital amaurosis 10 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Leber congenital amaurosis Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2020 | In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge - |
Bardet-Biedl syndrome 14 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Meckel syndrome, type 4 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 13, 2024 | - - |
Joubert syndrome 5 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;M;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.
REVEL
Benign
Sift
Benign
T;T;.
Sift4G
Benign
T;T;T
Polyphen
0.40
.;B;.
Vest4
MVP
MPC
0.13
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at