chr12-88086443-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_025114.4(CEP290):āc.4250A>Gā(p.Gln1417Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000687 in 1,600,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1417P) has been classified as Uncertain significance.
Frequency
Genomes: š 0.00027 ( 0 hom., cov: 33)
Exomes š: 0.000048 ( 0 hom. )
Consequence
CEP290
NM_025114.4 missense
NM_025114.4 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 5.71
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 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09907633).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CEP290 | NM_025114.4 | c.4250A>G | p.Gln1417Arg | missense_variant | 33/54 | ENST00000552810.6 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CEP290 | ENST00000552810.6 | c.4250A>G | p.Gln1417Arg | missense_variant | 33/54 | 1 | NM_025114.4 | P4 |
Frequencies
GnomAD3 genomes 0.000269 AC: 41AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000117 AC: 27AN: 230342Hom.: 0 AF XY: 0.0000885 AC XY: 11AN XY: 124288
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GnomAD4 exome AF: 0.0000476 AC: 69AN: 1448704Hom.: 0 Cov.: 30 AF XY: 0.0000459 AC XY: 33AN XY: 719242
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GnomAD4 genome 0.000269 AC: 41AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74344
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 25, 2014 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2021 | The c.4250A>G (p.Q1417R) alteration is located in exon 33 (coding exon 32) of the CEP290 gene. This alteration results from a A to G substitution at nucleotide position 4250, causing the glutamine (Q) at amino acid position 1417 to be replaced by an arginine (R). 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 26, 2024 | The CEP290 c.4250A>G variant is predicted to result in the amino acid substitution p.Gln1417Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.091% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. 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. | Apr 17, 2020 | - - |
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 | Oct 31, 2018 | - - |
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 18, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Uncertain
D;T;D
Polyphen
0.90
.;.;P
Vest4
MVP
MPC
0.35
ClinPred
T
GERP RS
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gMVP
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