rs386833981
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_006493.4(CLN5):c.625T>G(p.Tyr209Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 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 (★★).
Frequency
Consequence
NM_006493.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN5 | NM_006493.4 | c.625T>G | p.Tyr209Asp | missense_variant | Exon 4 of 4 | ENST00000377453.9 | NP_006484.2 | |
CLN5 | NM_001366624.2 | c.*74T>G | 3_prime_UTR_variant | Exon 5 of 5 | NP_001353553.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN5 | ENST00000377453.9 | c.625T>G | p.Tyr209Asp | missense_variant | Exon 4 of 4 | 1 | NM_006493.4 | ENSP00000366673.5 | ||
ENSG00000283208 | ENST00000638147.2 | c.565+4390T>G | intron_variant | Intron 3 of 4 | 5 | ENSP00000490953.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461724Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727146
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 5 Pathogenic:3
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Variant confirmed as disease-causing by referring clinical team -
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Neuronal ceroid lipofuscinosis Pathogenic:1
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 258 of the CLN5 protein (p.Tyr258Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive neuronal ceroid lipofuscinosis (PMID: 17607606, 28542837). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56545). 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 CLN5 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at