NM_000396.4:c.830C>T

Variant names:

• chr1-150799228-G-A
• rs74315304
• NM_000396.4:c.830C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000396.4(CTSK):​c.830C>T​(p.Ala277Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,426 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A277A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CTSK NM_000396.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 2.58
• Publications: 14 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 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000396.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-150799228-G-A is Pathogenic according to our data. Variant chr1-150799228-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8423.Status of the report is criteria_provided_single_submitter, 1 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.830C>T	p.Ala277Val	missense	Exon 7 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.830C>T	p.Ala277Val	missense	Exon 7 of 8	ENSP00000271651.3	P43235
	CTSK	ENST00000443913.2	TSL:3	c.1007C>T	p.Ala336Val	missense	Exon 7 of 8	ENSP00000405083.2	Q5QP40
	CTSK	ENST00000677887.1		c.872C>T	p.Ala291Val	missense	Exon 8 of 9	ENSP00000503876.1	A0A7I2V4B6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251462 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000110 AC: 16 AN: 1460426 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726640

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86218

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110666

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000171 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
4	-	-	Pyknodysostosis (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.95		Loss of disorder (P = 0.126)
MVP		0.98
MPC		1.0
ClinPred		0.95	D
GERP RS		6.2
Varity_R		0.89
gMVP		0.94
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.49		Position offset: 45

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

Other links and lift over

dbSNP: rs74315304; hg19: chr1-150771704;