chr1-150799228-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000396.4(CTSK):​c.830C>G​(p.Ala277Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A277V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CTSK NM_000396.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 0 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: G2P, PanelApp Australia, ClinGen, Orphanet, Genomics England PanelApp, Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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
• PM5: Other missense variant is known to change same aminoacid residue: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSK	NM_000396.4	MANE Select	c.830C>G	p.Ala277Gly	missense	Exon 7 of 8	NP_000387.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSK	ENST00000271651.8	TSL:1 MANE Select	c.830C>G	p.Ala277Gly	missense	Exon 7 of 8	ENSP00000271651.3
	CTSK	ENST00000443913.2	TSL:3	c.1007C>G	p.Ala336Gly	missense	Exon 7 of 8	ENSP00000405083.2
	CTSK	ENST00000677887.1		c.872C>G	p.Ala291Gly	missense	Exon 8 of 9	ENSP00000503876.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	0.49	N
PhyloP100		2.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	1.4	N
REVEL	Uncertain	0.49
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		1.0	D
Vest4		0.36
MutPred		0.88		Loss of stability (P = 0.0495)
MVP		0.97
MPC		1.0
ClinPred		0.86	D
GERP RS		6.2
Varity_R		0.76
gMVP		0.87
Mutation Taster		=48/52	disease causing

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: rs74315304; hg19: chr1-150771704;