rs150913606
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001042432.2(CLN3):c.649C>A(p.Leu217Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,612,634 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L217L) has been classified as Likely benign.
Frequency
Consequence
NM_001042432.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN3 | NM_001042432.2 | c.649C>A | p.Leu217Met | missense_variant | 9/16 | ENST00000636147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.649C>A | p.Leu217Met | missense_variant | 9/16 | 1 | NM_001042432.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000563 AC: 14AN: 248564Hom.: 0 AF XY: 0.0000445 AC XY: 6AN XY: 134822
GnomAD4 exome AF: 0.000128 AC: 187AN: 1460444Hom.: 1 Cov.: 32 AF XY: 0.000122 AC XY: 89AN XY: 726538
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74338
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
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 | Jul 23, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 217 of the CLN3 protein (p.Leu217Met). This variant is present in population databases (rs150913606, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CLN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 205112). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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