rs1057517252

Positions:

• chr1-150806780-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CTSK NM_000396.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.34

Genes affected

CTSK (HGNC:2536): (cathepsin K) The protein encoded by this gene is a lysosomal cysteine proteinase involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is predominantly expressed in osteoclasts. However, the encoded protein is also expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness. Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature. [provided by RefSeq, Apr 2013]

CTSK (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a signal_peptide (size 14) in uniprot entity CATK_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000396.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 1-150806780-A-G is Pathogenic according to our data. Variant chr1-150806780-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150806780-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSK	NM_000396.4	c.26T>C	p.Leu9Pro	missense_variant	2/8	ENST00000271651.8	NP_000387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSK	ENST00000271651.8	c.26T>C	p.Leu9Pro	missense_variant	2/8	1	NM_000396.4	ENSP00000271651.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyknodysostosis Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2024	Variant summary: CTSK c.26T>C (p.Leu9Pro) results in a non-conservative amino acid change located in the pre-region critical for transfer of the nascent protein to the endoplasmic reticulum (Nishi_1999). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251324 control chromosomes. c.26T>C has been reported in the literature as a biallelic genotype in individuals affected with Pyknodysostosis (example, Nishi_1999, Bae_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26402641, 17397052, 10571690, 25550899). ClinVar contains an entry for this variant (Variation ID: 371412). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 19, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2023	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.012	D;.
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.88		Loss of stability (P = 0.0254);.;
MVP		0.90
MPC		1.3
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.73
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057517252; hg19: chr1-150779256;