rs376493409
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025114.4(CEP290):c.4882C>T(p.Gln1628Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000393 in 1,552,940 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
Consequence
NM_025114.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CEP290 | NM_025114.4 | c.4882C>T | p.Gln1628Ter | stop_gained | 37/54 | ENST00000552810.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP290 | ENST00000552810.6 | c.4882C>T | p.Gln1628Ter | stop_gained | 37/54 | 1 | NM_025114.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000696 AC: 12AN: 172352Hom.: 0 AF XY: 0.0000986 AC XY: 9AN XY: 91254
GnomAD4 exome AF: 0.0000357 AC: 50AN: 1400756Hom.: 0 Cov.: 30 AF XY: 0.0000391 AC XY: 27AN XY: 691418
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74336
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2018 | The Q1628X nonsense variant in the CEP290 gene has been previously reported as a compound heterozygous change in individuals with CEP290-related disorders (Perrault et al., 2007, Chaki et al., 2011). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q1628X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, we interpret Q1628X as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | CEP290: PVS1, PM2, PM3 - |
Joubert syndrome 5 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 12, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2021 | The c.4882C>T (p.Q1628*) alteration, located in exon 37 (coding exon 36) of the CEP290 gene, consists of a C to T substitution at nucleotide position 4882. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 1628. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the CEP290 c.4882C>T alteration was observed in 0.01% (12/172352) of total alleles studied, with a frequency of 0.09% (8/8706) in the Ashkenazi Jewish subpopulation. The alteration has been reported in the compound heterozygous state in multiple patients with Leber congenital amaurosis and/or Joubert syndrome (Perrault, 2007; Brancati, 2007; Chaki, 2011; Wang, 2013; Summers, 2017; Feldhaus, 2020). Based on the available evidence, this alteration is classified as pathogenic. - |
Occipital encephalocele;C1834931:Cystic renal dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Bardet-Biedl syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 26, 2023 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Gln1628*) 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 (rs376493409, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome or Leber congenital amaurosis (PMID: 17345604, 21866095, 26092869, 28497568). ClinVar contains an entry for this variant (Variation ID: 217635). For these reasons, this variant has been classified as 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
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Blindness;C0557874:Global developmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Aug 26, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at