13-76995077-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5
The NM_006493.4(CLN5):c.188G>C(p.Arg63Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006493.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.188G>C | p.Arg63Pro | missense_variant | 2/4 | ENST00000377453.9 | |
CLN5 | NM_001366624.2 | c.188G>C | p.Arg63Pro | missense_variant | 2/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.188G>C | p.Arg63Pro | missense_variant | 2/4 | 1 | NM_006493.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 5 Pathogenic:2
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2022 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 112 of the CLN5 protein (p.Arg112Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 16814585). ClinVar contains an entry for this variant (Variation ID: 56533). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLN5 function (PMID: 20052765). This variant disrupts the p.Arg112 amino acid residue in CLN5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15728307, 20052765, 30078242). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at