rs371277428

Positions:

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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CTSK
NM_000396.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.45

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a propeptide Activation peptide (size 98) in uniprot entity CATK_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) 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 chr1-150806208-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1066193.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 1-150806209-G-A is Pathogenic according to our data. Variant chr1-150806209-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150806209-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSK	NM_000396.4 linkuse as main transcript	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 linkuse as main transcript	c.136C>T	p.Arg46Trp	missense_variant	3/8	1	NM_000396.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

249808

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135146

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000263

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyknodysostosis

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 29, 2017	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.136C>T(p.Arg46Trp) has been reported in homozygous state in multiple unrelated individuals affected with Pycnodysostosis (Pangrazio A, et. al., 2014; Mandal K, et. al., 2016). The variant has been reported with allele frequency of 0.003% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely pathogenic/Pathogenic. The amino acid change p.Arg46Trp in CTSK is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;.

Vest4

0.99

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

5.6

Varity_R

0.94

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: 15

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over