rs386833966
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_006493.4(CLN5):βc.936delβ(p.Phe312LeufsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000311 in 1,609,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000027 ( 0 hom. )
Consequence
CLN5
NM_006493.4 frameshift
NM_006493.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.04
Genes affected
CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]
FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-77000823-AT-A is Pathogenic according to our data. Variant chr13-77000823-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 56528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.936del | p.Phe312LeufsTer4 | frameshift_variant | 4/4 | ENST00000377453.9 | |
CLN5 | NM_001366624.2 | c.*385del | 3_prime_UTR_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.936del | p.Phe312LeufsTer4 | frameshift_variant | 4/4 | 1 | NM_006493.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 246982Hom.: 0 AF XY: 0.0000225 AC XY: 3AN XY: 133396
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1457226Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3AN XY: 724576
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 5 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 21, 2023 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 13, 2022 | Variant summary: CLN5 c.936delT (p.Phe312LeufsX4) 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 1.2e-05 in 246982 control chromosomes. c.1083delT has been reported in the literature as a homozygous genotype in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and has been subsequently cited by others (example, Xin_2010, Ge_2018, Kousi_2012, Luo_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change creates a premature translational stop signal (p.Phe361Leufs*4) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs386833966, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (NCL) (PMID: 20157158). ClinVar contains an entry for this variant (Variation ID: 56528). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406, 11971870, 20052765, 24038957, 24058541). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at