rs146579299
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBS1_Supporting
The NM_018941.4(CLN8):c.779C>T(p.Pro260Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P260P) has been classified as Likely benign.
Frequency
Consequence
NM_018941.4 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 |
---|---|---|---|---|---|---|---|
CLN8 | NM_018941.4 | c.779C>T | p.Pro260Leu | missense_variant | 3/3 | ENST00000331222.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN8 | ENST00000331222.6 | c.779C>T | p.Pro260Leu | missense_variant | 3/3 | 1 | NM_018941.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000651 AC: 99AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000227 AC: 57AN: 251410Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135878
GnomAD4 exome AF: 0.000107 AC: 157AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000811 AC XY: 59AN XY: 727244
GnomAD4 genome AF: 0.000657 AC: 100AN: 152304Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 21, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Neuronal ceroid lipofuscinosis 8;C1864923:Neuronal ceroid lipofuscinosis 8 northern epilepsy variant Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Bioinformatics Unit, Institut Pasteur de Montevideo | Feb 29, 2024 | The two variants found can be classified as likely pathogenic according to ACMG criteria: i. Pro260Leu missense variant has low frequency (PM2), detected in trans with another likely pathogenic mutation (PM3), is a missense variant in a gene where missense variants are a common mechanism of disease (PP2). Additionally, multiple lines of evidence of computational in silico scores support a deleterious effect (PP3), the patient's phenotype is highly specific for a disease with a single gene etiology (PP4). Hence, 2 PM and 3 PP, leads to a likely pathogenic classification; ii. Val261Ala missense variant can also be classified as likely pathogenic with the same rules applied. We have identified the two variants in compound heterozygosity with additional data to consider them as likely pathogenic mutations. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Nov 11, 2021 | CLN8 NM_018941 exon 3 p.Pro260Leu (c.779C>T): This variant has not been reported in the literature but is present in 64/24030 African individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs146579299). This variant is present in ClinVar (Variation ID:205196). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Neuronal ceroid lipofuscinosis 8 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 25, 2020 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Neuronal ceroid lipofuscinosis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at