NM_025114.4:c.2052+1_2052+2delGT
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_025114.4(CEP290):c.2052+1_2052+2delGT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 1,537,196 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_025114.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000205 AC: 3AN: 146660Hom.: 0 AF XY: 0.0000259 AC XY: 2AN XY: 77258
GnomAD4 exome AF: 0.0000484 AC: 67AN: 1385056Hom.: 0 AF XY: 0.0000410 AC XY: 28AN XY: 682894
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Canonical splice site variant predicted to result in a null allele 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: 31589614, 27535533, 23847139, 32865313) -
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Retinal dystrophy Pathogenic:2
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CEP290-related disorder Pathogenic:1
The CEP290 c.2052+1_2052+2delGT variant is predicted to result in a deletion affecting a canonical splice site. This variant was reported along with a second pathogenic variant in individuals with non-syndromic Leber congenital amaurosis and in one patient with Joubert syndrome (Wang et al. 2013. PubMed ID: 23847139; Sallum et al. 2020. PubMed ID: 32865313). This variant is reported in 0.0051% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt splicing in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Leber congenital amaurosis 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 affects a splice site in intron 20 of the CEP290 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is present in population databases (rs747835249, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with Leber congenital amaurosis (LCA) (PMID: 23847139, 28510626, 28660274). ClinVar contains an entry for this variant (Variation ID: 236466). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at