rs535755345
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006493.4(CLN5):c.704T>C(p.Val235Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V235V) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CLN5
NM_006493.4 missense
NM_006493.4 missense
Scores
5
5
4
Clinical Significance
Conservation
PhyloP100: 6.25
Genes affected
CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]
FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.704T>C | p.Val235Ala | missense_variant | 4/4 | ENST00000377453.9 | |
CLN5 | NM_001366624.2 | c.*153T>C | 3_prime_UTR_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.704T>C | p.Val235Ala | missense_variant | 4/4 | 1 | NM_006493.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251348Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135876
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461858Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727226
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 5 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN5 protein function. ClinVar contains an entry for this variant (Variation ID: 457968). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. This variant is present in population databases (rs535755345, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 284 of the CLN5 protein (p.Val284Ala). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Polyphen
0.99
.;D
MutPred
0.41
.;Loss of stability (P = 0.0403);
MVP
0.98
MPC
0.27
ClinPred
D
GERP RS
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at