rs386833970
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006493.4(CLN5):c.144dup(p.Ser49LeufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I47I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006493.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.144dup | p.Ser49LeufsTer13 | frameshift_variant | 1/4 | ENST00000377453.9 | |
CLN5 | NM_001366624.2 | c.144dup | p.Ser49LeufsTer13 | frameshift_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.144dup | p.Ser49LeufsTer13 | frameshift_variant | 1/4 | 1 | NM_006493.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.96e-7 AC: 1AN: 1436028Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 713664
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 | Fulgent Genetics, Fulgent Genetics | May 14, 2022 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | This sequence change creates a premature translational stop signal (p.Ser98Leufs*13) in the CLN5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN5 are known to be pathogenic (PMID: 20157158). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis type 5 (CLN5) (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 56532). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2021 | Variant summary: CLN5 c.291dupC (p.Ser98LeufsX13) 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 203636 control chromosomes. c.291dupC has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Kousi_2012, Kohan_2015) and has also been subsequently cited by others. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at