Variant rs762212949 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000396.4(CTSK):c.263A>T(p.Gln88Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q88P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CTSK
NM_000396.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.506

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:

CTSK (HGNC:):

CTSK links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.3616882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSK	NM_000396.4 linkuse as main transcript	c.263A>T	p.Gln88Leu	missense_variant	4/8	ENST00000271651.8	NP_000387.1	P43235

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSK	ENST00000271651.8 linkuse as main transcript	c.263A>T	p.Gln88Leu	missense_variant	4/8	1	NM_000396.4	ENSP00000271651.3		P43235

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251436

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

D;T

Eigen

Benign

-0.0042

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.55

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.36

T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.5

L;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.025

D;D

Sift4G

Benign

0.10

T;.

Polyphen

0.0

B;.

Vest4

0.49

MutPred

0.38

Loss of disorder (P = 0.0445);.;

MVP

0.99

MPC

0.30

ClinPred

0.86

GERP RS

4.3

Varity_R

0.62

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over