rs149308952
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_018941.4(CLN8):āc.470A>Gā(p.His157Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,022 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H157Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_018941.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN8 | NM_018941.4 | c.470A>G | p.His157Arg | missense_variant | 2/3 | ENST00000331222.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN8 | ENST00000331222.6 | c.470A>G | p.His157Arg | missense_variant | 2/3 | 1 | NM_018941.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251458Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727248
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Neuronal ceroid lipofuscinosis 8 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 22, 2015 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | Jul 21, 2016 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2022 | Variant summary: CLN8 c.470A>G (p.His157Arg) results in a non-conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251458 control chromosomes (gnomAD). c.470A>G has been reported in the literature in one heterozygous individual affected with Cerebellar Atrophy (Sun_2019), and in one homozygous individual affected with Neuronal Ceroid-Lipofuscinosis (e.g. Kousi_2009, Reinhardt_2010). These data indicate that the variant may be associated with disease. Functional evaluation of the variant protein showed that there was signficantly reduced interaction with lysosomal proteins, with the most pronounced variant effect resulting in <10% of normal activity (di Ronza_2018). Two ClinVar submitters have assessed the variant since 2014 without evidence for independent evaluation: one classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 09, 2022 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 157 of the CLN8 protein (p.His157Arg). This variant is present in population databases (rs149308952, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of CLN8-related conditions (PMID: 19807737, 29915382). ClinVar contains an entry for this variant (Variation ID: 210736). 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 expected to disrupt CLN8 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