rs74315305

Positions:

• chr1-150806109-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000396.4(CTSK):​c.236G>A​(p.Gly79Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G79R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CTSK NM_000396.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.69

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 18 ACMG points.

• PM1: In a turn (size 3) in uniprot entity CATK_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000396.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-150806110-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1683244.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 1-150806109-C-T is Pathogenic according to our data. Variant chr1-150806109-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150806109-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSK	NM_000396.4	c.236G>A	p.Gly79Glu	missense_variant	3/8	ENST00000271651.8	NP_000387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSK	ENST00000271651.8	c.236G>A	p.Gly79Glu	missense_variant	3/8	1	NM_000396.4	ENSP00000271651.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyknodysostosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 23, 2024	Variant summary: CTSK c.236G>A (p.Gly79Glu) results in a non-conservative amino acid change located in the Cathepsin propeptide inhibitor domain (IPR013201) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251314 control chromosomes. c.236G>A has been reported in the literature in individuals affected with Pyknodysostosis (examples: Haagerup_2000, Ho_1999, Hou_1999, Sait_2021). These data indicate that the variant is likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (Hou_1999, Roy_2018). The most pronounced variant effect results in the absence of protease activity. The following publications have been ascertained in the context of this evaluation (PMID: 10878663, 10491211, 10074491, 30199612, 33945887). ClinVar contains an entry for this variant (Variation ID: 8424). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 03, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	H;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.95		Gain of disorder (P = 0.0435);.;
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.96

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: rs74315305; hg19: chr1-150778585;