rs386834158
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025114.4(CEP290):c.5493delA(p.Ala1832ProfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,563,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_025114.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151748Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000224 AC: 5AN: 223598Hom.: 0 AF XY: 0.0000247 AC XY: 3AN XY: 121346
GnomAD4 exome AF: 0.0000149 AC: 21AN: 1412148Hom.: 0 Cov.: 27 AF XY: 0.0000128 AC XY: 9AN XY: 702784
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151748Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74090
ClinVar
Submissions by phenotype
not provided Pathogenic:5
CEP290: PVS1, PM2, PM3 -
Reported previously in association with CEP290-related disorders (PMID: 21245082, 19466712, 19764032); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34196655, 32531858, 34906470, 17564967, 17705300, 19466712, 19764032, 28041643, 31734136, 32581362, 31589614, 34426522, 35906228, 21245082, 36803942, 37224330) -
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Meckel syndrome, type 4 Pathogenic:3
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Variant summary: CEP290 c.5493delA (p.Ala1832ProfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.2e-05 in 223598 control chromosomes. c.5493delA has been reported in the literature in individuals affected with Joubert syndromerelated disorders, retinal dystrophy, or Leber congenital amaurosis (Brancati_2007, Carss_2017, Feldhaus_2020). These data indicate that the variant may be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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CEP290-related disorder Pathogenic:2
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The CEP290 c.5493delA variant is predicted to result in a frameshift and premature protein termination (p.Ala1832Profs*19). This variant has been reported in individuals with Joubert Syndrome and related disorders (Brancati et al. 2007. PubMed ID: 17564967; Frank et al. 2008. PubMed ID: 17705300) or inherited retinal dystrophy (Carss et al. 2017. PubMed ID: 28041643, Patient G001347 in Supplemental Table S2). This variant is reported in 0.0049% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Retinal dystrophy Pathogenic:2
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Joubert syndrome 5 Pathogenic:2
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5. -
This variant was identified as compound heterozygous with NM_025114.4:c.2279_2280del. -
Leber congenital amaurosis 10 Pathogenic:1
The CEP290 c.5493del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP1, PVS1. Based on this evidence we have classified this variant as Pathogenic. -
Leber congenital amaurosis Pathogenic:1
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Polycystic kidney disease;C0266292:Abnormality of the kidney;C0431399:Familial aplasia of the vermis;C1840379:Cerebellar vermis hypoplasia;C1847762:Cerebellar cyst;C3275899:Hyperechogenic kidneys Pathogenic:1
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Bardet-Biedl syndrome 14 Pathogenic:1
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Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ala1832Profs*19) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Leber congenital amaurosis and/or Meckel-Gruber syndrome (PMID: 17705300, 20683928, 21245082). This variant is also known as 5489_5493delA, c.5489del and p.Gln1830fs. ClinVar contains an entry for this variant (Variation ID: 56739). 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 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at