16-28482102-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001042432.2(CLN3):c.1056+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001042432.2 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN3 | NM_001042432.2 | c.1056+3A>C | splice_region_variant, intron_variant | Intron 14 of 15 | ENST00000636147.2 | NP_001035897.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.1056+3A>C | splice_region_variant, intron_variant | Intron 14 of 15 | 1 | NM_001042432.2 | ENSP00000490105.1 | |||
ENSG00000261832 | ENST00000637378.1 | c.228+3A>C | splice_region_variant, intron_variant | Intron 4 of 9 | 5 | ENSP00000490831.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1458316Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2AN XY: 725278
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 3 Pathogenic:3
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Neuronal ceroid lipofuscinosis Pathogenic:2
Variant summary: CLN3 c.1056+3A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Lojewski_2014). The variant was absent in 243644 control chromosomes (gnomAD). c.1056+3A>C has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Kousi_2012, Lojewski_2014, Wright_2020) or isolated retinal degeneration (Smirnov_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24271013, 21990111, 33507216, 31926949). ClinVar contains an entry for this variant (Variation ID: 56247). Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change falls in intron 14 of the CLN3 gene. It does not directly change the encoded amino acid sequence of the CLN3 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of CLN3-related conditions (PMID: 24271013; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56247). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CLN3 function (PMID: 24271013). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at