15-68218584-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017882.3(CLN6):c.150C>G(p.Tyr50*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017882.3 stop_gained
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN6 | NM_017882.3 | c.150C>G | p.Tyr50* | stop_gained | Exon 2 of 7 | ENST00000249806.11 | NP_060352.1 | |
CLN6 | NM_001411068.1 | c.246C>G | p.Tyr82* | stop_gained | Exon 2 of 7 | NP_001397997.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135882
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461738Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727166
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
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Reported previously in a patient with a clinical diagnosis of Kufs disease who was also heterozygous for two missense substitutions in the CLN6 gene, although no further clinical details were provided and parental testing was not performed to determine the phase of the three variants (PMID: 21549341); Reported previously as a pathogenic variant in a cohort of patients referred for epilepsy genetic testing; however, no specific clinical information was provided (PMID: 31440721); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 31440721, 26075876, 33024953, 21549341) -
CLN6: PVS1, PM2, PM3 -
Neuronal ceroid lipofuscinosis Pathogenic:2
Variant summary: CLN6 c.150C>G (p.Tyr50X) 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 associated with Neuronal Ceroid Lipofuscinosis (NCL) in HGMD. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.150C>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (DiFruscio_2015), and specifically in Kufs disease, a subtype of NCL (Arsov_2011, Talbot_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
This sequence change creates a premature translational stop signal (p.Tyr50*) in the CLN6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN6 are known to be pathogenic (PMID: 19135028). This variant is present in population databases (rs154774640, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21549341, 26075876). ClinVar contains an entry for this variant (Variation ID: 68094). For these reasons, this variant has been classified as Pathogenic. -
Ceroid lipofuscinosis, neuronal, 6A Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at