rs386834136
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_018941.4(CLN8):c.661G>A(p.Gly221Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G221G) has been classified as Likely benign.
Frequency
Consequence
NM_018941.4 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 |
---|---|---|---|---|---|---|---|
CLN8 | NM_018941.4 | c.661G>A | p.Gly221Ser | missense_variant | 3/3 | ENST00000331222.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN8 | ENST00000331222.6 | c.661G>A | p.Gly221Ser | missense_variant | 3/3 | 1 | NM_018941.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251482Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135920
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38AN XY: 727248
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74366
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 8 Pathogenic:1Uncertain:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 10, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 15, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 12, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 01, 2021 | Variant summary: CLN8 c.661G>A (p.Gly221Ser) results in a non-conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251482 control chromosomes (gnomAD). This frequency is lower than the maximum expected for a pathogenic variant in CLN8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00087), allowing no conclusion about variant significance. c.661G>A has been reported in the literature in an individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease), however no phenotype details were provided (Kousi_2012). This report does not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). 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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 23, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 221 of the CLN8 protein (p.Gly221Ser). This variant is present in population databases (rs386834136, gnomAD 0.01%). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofucinosis (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 56717). 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 not expected to disrupt CLN8 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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