rs144656959
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBS1_Supporting
The NM_006493.4(CLN5):c.459G>A(p.Met153Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006493.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.459G>A | p.Met153Ile | missense_variant | 3/4 | ENST00000377453.9 | |
CLN5 | NM_001366624.2 | c.459G>A | p.Met153Ile | missense_variant | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.459G>A | p.Met153Ile | missense_variant | 3/4 | 1 | NM_006493.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000591 AC: 90AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000553 AC: 139AN: 251490Hom.: 0 AF XY: 0.000581 AC XY: 79AN XY: 135920
GnomAD4 exome AF: 0.000956 AC: 1398AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.000958 AC XY: 697AN XY: 727242
GnomAD4 genome ? AF: 0.000584 AC: 89AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35AN XY: 74474
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 12, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2023 | Reported in the heterozygous state in two unrelated individuals who were suspected to have a lysosomal storage disorder; a second CLN5 variant was not identified, and no additional information was provided (Fernandez-Marmiesse et al., 2014).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24767253) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 29, 2015 | - - |
Neuronal ceroid lipofuscinosis 5 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2024 | The c.606G>A (p.M202I) alteration is located in exon 3 (coding exon 3) of the CLN5 gene. This alteration results from a G to A substitution at nucleotide position 606, causing the methionine (M) at amino acid position 202 to be replaced by an isoleucine (I). Based on data from the Genome Aggregation Database (gnomAD) database, the CLN5 c.606G>A alteration was observed in 0.05% (146/282884) of total alleles studied, with a frequency of 0.1% (126/129190) in the European (non-Finnish) subpopulation. This variant was identified in two individuals with a clinical suspicion of a lysosomal storage disease; however, no second CLN5 variants were identified (Fernández-Marmiesse, 2014). This amino acid position is not well conserved in available vertebrate species. The p.M202I alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 202 of the CLN5 protein (p.Met202Ile). This variant is present in population databases (rs144656959, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lysosomal storage disease (PMID: 24767253). ClinVar contains an entry for this variant (Variation ID: 205145). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN5 protein function. 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