rs201225986
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP7
The NM_001042432.2(CLN3):āc.222T>Cā(p.His74=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,607,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001042432.2 splice_region, synonymous
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.222T>C | p.His74= | splice_region_variant, synonymous_variant | 4/16 | ENST00000636147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.222T>C | p.His74= | splice_region_variant, synonymous_variant | 4/16 | 1 | NM_001042432.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000685 AC: 17AN: 248016Hom.: 0 AF XY: 0.0000597 AC XY: 8AN XY: 134078
GnomAD4 exome AF: 0.000107 AC: 155AN: 1455380Hom.: 0 Cov.: 30 AF XY: 0.000102 AC XY: 74AN XY: 724126
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74302
ClinVar
Submissions by phenotype
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Neuronal ceroid lipofuscinosis Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 05, 2022 | This sequence change affects codon 74 of the CLN3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CLN3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201225986, gnomAD 0.02%). 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: 457951). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 24, 2020 | - - |
Neuronal ceroid lipofuscinosis 3 Uncertain:2
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at