rs373913704
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_025114.4(CEP290):c.226G>A(p.Ala76Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000763 in 1,597,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00078 ( 1 hom. )
Consequence
CEP290
NM_025114.4 missense
NM_025114.4 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 6.23
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 Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04635045).
BP6
Variant 12-88139519-C-T is Benign according to our data. Variant chr12-88139519-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166841.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10}. Variant chr12-88139519-C-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CEP290 | NM_025114.4 | c.226G>A | p.Ala76Thr | missense_variant | 4/54 | ENST00000552810.6 | NP_079390.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CEP290 | ENST00000552810.6 | c.226G>A | p.Ala76Thr | missense_variant | 4/54 | 1 | NM_025114.4 | ENSP00000448012.1 |
Frequencies
GnomAD3 genomes 0.000560 AC: 85AN: 151892Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000629 AC: 150AN: 238306Hom.: 0 AF XY: 0.000641 AC XY: 83AN XY: 129488
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GnomAD4 exome AF: 0.000784 AC: 1133AN: 1445078Hom.: 1 Cov.: 30 AF XY: 0.000820 AC XY: 589AN XY: 718542
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GnomAD4 genome 0.000559 AC: 85AN: 152010Hom.: 0 Cov.: 33 AF XY: 0.000633 AC XY: 47AN XY: 74286
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | CEP290: PM2, PP3 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27323230, 25920555, 32036094, 33308271) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 30, 2014 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 05, 2021 | DNA sequence analysis of the CEP290 gene demonstrated a sequence change, c.226G>A, in exon 4 that results in an amino acid change, p.Ala76Thr. This sequence change does not appear to have been previously described in patients with CEP290-related disorders and has been described in the gnomAD database with a low population frequency of 0.25% in Ashkenazi Jews subpopulation (dbSNP rs373913704). The p.Ala76Thr change affects a moderately conserved amino acid residue located in a domain of the CEP290 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala76Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala76Thr change remains unknown at this time. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 01, 2022 | Variant summary: CEP290 c.226G>A (p.Ala76Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 238306 control chromosomes, predominantly at a frequency of 0.00093 within the Non-Finnish European subpopulation in the gnomAD database, however in certain subpopulations e.g. in the Estonians, Bulgarians and Ashkenazi Jewish, the variant occurred with an even higher frequency, 0.0025-0.0029, which might suggest a benign role for the variant. The variant, c.226G>A, has been reported in the literature in heterozygous state in individuals affected with various disease phenotypes e.g. Joubert syndrome, Leber congenital amaurosis and cone-rod dystrophy, however in at least two of these cases other (potentially) pathogenic variants were also noted to co-occur (Kroes_2015, Skorczyk-Werner_2020, Rodriguez-Munoz_2020). These reports do not provide unequivocal conclusions about association of the variant with CEP290-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Senior-Loken syndrome 6 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
CEP290-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 30, 2024 | The CEP290 c.226G>A variant is predicted to result in the amino acid substitution p.Ala76Thr. This variant has been reported in the heterozygous state in two individuals with Joubert syndrome (Kroes et al. 2016. PubMed ID: 25920555, Supplementary Table S2). This variant has also been reported in the heterozygous state in an individual with Leber congenital amaurosis; however, this individual also harbored additional variants in another gene (Skorczyk-Werner et al. 2020. PubMed: 33308271, Table 2). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish 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. - |
Leber congenital amaurosis 10 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Bardet-Biedl syndrome 14 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Meckel syndrome, type 4 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Joubert syndrome 5 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
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 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N;.
REVEL
Uncertain
Sift
Benign
D;D;.;T;.
Sift4G
Benign
T;T;T;T;D
Polyphen
1.0
.;D;.;.;.
Vest4
MVP
MPC
0.34
ClinPred
T
GERP RS
Varity_R
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