rs371277428
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000396.4(CTSK):c.136C>T(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,836 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46Q) 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.136C>T | p.Arg46Trp | missense_variant | 3/8 | ENST00000271651.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTSK | ENST00000271651.8 | c.136C>T | p.Arg46Trp | missense_variant | 3/8 | 1 | NM_000396.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 249808Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135146
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461728Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727170
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
Pyknodysostosis Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 07, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 03, 2023 | Variant summary: CTSK c.136C>T (p.Arg46Trp) results in a non-conservative amino acid change located in the Cathepsin propeptide inhibitor domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249808 control chromosomes. c.136C>T has been reported in the literature in multiple individuals affected with Pyknodysostosis or osteopetrosis. These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 29, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.136C>T (p.Arg46Trp) has been observed to segregate with pycnodysostosis in a family and has also been observed to be homozygous in unrelated in individuals (Pangrazio A et al., 2014). The p.Arg46Trp variant has been submitted allele frequency 0.003% in genomAD exomes and novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely_pathogenic. The amino acid Arg at position 46 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg46Trp in CTSK is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the CTSK protein (p.Arg46Trp). This variant is present in population databases (rs371277428, gnomAD 0.02%). This missense change has been observed in individuals with pycnodysostosis in a family and has also been observed to be homozygous in unrelated in individuals (PMID: 17206399, 24269275, 27092432). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553560). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at