rs29001685
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000396.4(CTSK):āc.926T>Cā(p.Leu309Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,054 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L309F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000396.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTSK | NM_000396.4 | c.926T>C | p.Leu309Pro | missense_variant | 8/8 | ENST00000271651.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTSK | ENST00000271651.8 | c.926T>C | p.Leu309Pro | missense_variant | 8/8 | 1 | NM_000396.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251468Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135910
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461856Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Pyknodysostosis Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 17, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2000 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 19, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu309 amino acid residue in CTSK. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 CTSK protein function. ClinVar contains an entry for this variant (Variation ID: 8426). This missense change has been observed in individual(s) with pycnodysostosis (PMID: 10878663). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs29001685, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 309 of the CTSK protein (p.Leu309Pro). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at