rs74315305

Variant names:

• chr1-150806109-C-T
• rs74315305
• NM_000396.4:c.236G>A

Variant summary

Our verdict is Pathogenic. The variant received 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:4
• Conservation: PhyloP100: 2.69
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• pycnodysostosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Ambry Genetics, Genomics England PanelApp, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a propeptide Activation peptide (size 98) in uniprot entity CATK_HUMAN there are 5 pathogenic changes around while only 1 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 chr1-150806110-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1683244.
• 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 VariationId is 8424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000396.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSK	NM_000396.4	MANE Select	c.236G>A	p.Gly79Glu	missense	Exon 3 of 8	NP_000387.1	P43235

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSK	ENST00000271651.8	TSL:1 MANE Select	c.236G>A	p.Gly79Glu	missense	Exon 3 of 8	ENSP00000271651.3	P43235
	CTSK	ENST00000443913.2	TSL:3	c.413G>A	p.Gly138Glu	missense	Exon 3 of 8	ENSP00000405083.2	Q5QP40
	CTSK	ENST00000677887.1		c.278G>A	p.Gly93Glu	missense	Exon 4 of 9	ENSP00000503876.1	A0A7I2V4B6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Pyknodysostosis (4)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		2.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	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
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs74315305; hg19: chr1-150778585;