rs1057517252
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000396.4(CTSK):c.26T>C(p.Leu9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,816 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L9L) has been classified as Likely benign.
Frequency
Consequence
NM_000396.4 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTSK | NM_000396.4 | c.26T>C | p.Leu9Pro | missense_variant | 2/8 | ENST00000271651.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTSK | ENST00000271651.8 | c.26T>C | p.Leu9Pro | missense_variant | 2/8 | 1 | NM_000396.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727218
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Pyknodysostosis Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 19, 2016 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2023 | ClinVar contains an entry for this variant (Variation ID: 371412). This missense change has been observed in individuals with pycnodysostosis (PMID: 10571690, 10634420). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 9 of the CTSK protein (p.Leu9Pro). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. Studies have shown that this missense change alters CTSK gene expression (PMID: 10634420). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at