NM_006493.4:c.924_925delCT
Variant names:
Variant summary
Our verdict is . The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
Pathogenic
The NM_006493.4(CLN5):c.924_925delCT(p.Leu309AlafsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
CLN5
NM_006493.4 frameshift
NM_006493.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.56
Publications
6 publications found
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]
ENSG00000283208 (HGNC:):
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]
FBXL3 Gene-Disease associations (from GenCC):
- intellectual disability, short stature, facial anomalies, and joint dislocationsInheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics
Genome browser will be placed here
new If you want to explore the variant's impact on the transcript NM_006493.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-77000812-GTC-G is Pathogenic according to our data. Variant chr13-77000812-GTC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 56526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_006493.4. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CLN5 | TSL:1 MANE Select | c.924_925delCT | p.Leu309AlafsTer4 | frameshift | Exon 4 of 4 | ENSP00000366673.5 | O75503 | ||
| CLN5 | TSL:1 | c.924_925delCT | p.Leu309AlafsTer4 | frameshift | Exon 4 of 4 | ENSP00000490181.2 | O75503 | ||
| ENSG00000283208 | TSL:5 | c.565+4689_565+4690delCT | intron | N/A | ENSP00000490953.2 | A0A1B0GWJ7 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152188
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
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Gnomad FIN
AF:
Gnomad MID
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Gnomad NFE
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Gnomad OTH
AF:
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
1
AN:
152188
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74338
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41456
American (AMR)
AF:
AC:
1
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5202
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
0
AN:
10598
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68028
Other (OTH)
AF:
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
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0
1
1
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0.95
Allele balance
Age Distribution
Genome Het
Variant carriers
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Age
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Neuronal ceroid lipofuscinosis 5 (3)
1
-
-
Neuronal ceroid lipofuscinosis (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs386833964 ;
hg19: chr13-77574947;