13-76995064-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_006493.4(CLN5):c.175C>T(p.Arg59Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000616 in 1,460,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006493.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.175C>T | p.Arg59Cys | missense_variant, splice_region_variant | Exon 2 of 4 | ENST00000377453.9 | NP_006484.2 | |
CLN5 | NM_001366624.2 | c.175C>T | p.Arg59Cys | missense_variant, splice_region_variant | Exon 2 of 5 | NP_001353553.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.175C>T | p.Arg59Cys | missense_variant, splice_region_variant | Exon 2 of 4 | 1 | NM_006493.4 | ENSP00000366673.5 | ||
ENSG00000283208 | ENST00000638147.2 | c.175C>T | p.Arg59Cys | missense_variant, splice_region_variant | Exon 2 of 5 | 5 | ENSP00000490953.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250754Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135508
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460944Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726754
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis Uncertain:2
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This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 108 of the CLN5 protein (p.Arg108Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 451777). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Neuronal ceroid lipofuscinosis 5 Uncertain:1
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not provided Uncertain:1
A variant of uncertain significance has been identified in the CLN5 gene. The R108C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R108C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R108C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at