1-150796813-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000396.4(CTSK):c.976T>G(p.Phe326Val) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSK NM_000396.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Cathepsin K (size 214) in uniprot entity CATK_HUMAN there are 45 pathogenic changes around while only 2 benign (96%) in NM_000396.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSK	NM_000396.4	c.976T>G	p.Phe326Val	missense_variant	8/8	ENST00000271651.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSK	ENST00000271651.8	c.976T>G	p.Phe326Val	missense_variant	8/8	1	NM_000396.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2021

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 326 of the CTSK protein (p.Phe326Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CTSK-related conditions. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.97	D
Vest4		0.51
MutPred		0.80		Loss of stability (P = 0.0496);
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.91
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-150769289;