chr13-77000844-CACAA-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_006493.4(CLN5):c.956_959delAACA(p.Lys319SerfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000118 in 1,605,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_006493.4 frameshift
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 |
---|---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.956_959delAACA | p.Lys319SerfsTer15 | frameshift_variant | Exon 4 of 4 | ENST00000377453.9 | NP_006484.2 | |
CLN5 | NM_001366624.2 | c.*405_*408delAACA | 3_prime_UTR_variant | Exon 5 of 5 | NP_001353553.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.956_959delAACA | p.Lys319SerfsTer15 | frameshift_variant | Exon 4 of 4 | 1 | NM_006493.4 | ENSP00000366673.5 | ||
ENSG00000283208 | ENST00000638147.2 | c.565+4721_565+4724delAACA | intron_variant | Intron 3 of 4 | 5 | ENSP00000490953.2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1452844Hom.: 0 AF XY: 0.0000111 AC XY: 8AN XY: 722110
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 5 Pathogenic:5
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Neuronal ceroid lipofuscinosis Pathogenic:3
Variant summary: CLN5 c.956_959delAACA (p.Lys319SerfsX15) 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 was absent in 243956 control chromosomes. c.1103_1106delAACA has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Kohan_2015, Ren_2019, Xin_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change creates a premature translational stop signal (p.Lys368Serfs*15) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs386833967, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid liopfuscinosis (PMID: 20157158, 20960652, 22532218, 25976102; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1002_1006delAACA. ClinVar contains an entry for this variant (Variation ID: 56529). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation, as the last 40 amino acids are replaced with 14 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31105743, 20157158, 32983231, 21990111, 22532218, 20960652) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at