1-150805997-T-C

Variant names:

• chr1-150805997-T-C
• rs762212949
• NM_000396.4:c.263A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000396.4(CTSK):​c.263A>G​(p.Gln88Arg) 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. 13/22 in silico tools predict 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.506
• 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Ambry Genetics, Genomics England PanelApp, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.18951926).

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.263A>G	p.Gln88Arg	missense	Exon 4 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.263A>G	p.Gln88Arg	missense	Exon 4 of 8	ENSP00000271651.3	P43235
	CTSK	ENST00000443913.2	TSL:3	c.440A>G	p.Gln147Arg	missense	Exon 4 of 8	ENSP00000405083.2	Q5QP40
	CTSK	ENST00000677887.1		c.305A>G	p.Gln102Arg	missense	Exon 5 of 9	ENSP00000503876.1	A0A7I2V4B6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	0.21	N
PhyloP100		0.51
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.32
Sift	Benign	0.16	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.29		Gain of MoRF binding (P = 0.0451)
MVP		0.96
MPC		0.33
ClinPred		0.38	T
GERP RS		4.3
Varity_R		0.47
gMVP		0.42
Mutation Taster		=73/27	polymorphism

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: rs762212949; hg19: chr1-150778473;