NM_000396.4:c.-2+108A>G

Variant names:

• chr1-150808106-T-C
• rs4379678
• NM_000396.4:c.-2+108A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000396.4(CTSK):​c.-2+108A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0739 in 152,310 control chromosomes in the GnomAD database, including 585 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.074 (585 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTSK NM_000396.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• Publications: 17 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

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.-2+108A>G		intron	N/A	NP_000387.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSK	ENST00000271651.8	TSL:1 MANE Select	c.-2+108A>G		intron	N/A	ENSP00000271651.3
	CTSK	ENST00000480670.2	TSL:3	n.1308A>G		non_coding_transcript_exon	Exon 1 of 6
	CTSK	ENST00000679171.1		n.600A>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0739 AC: 11250 AN: 152192 Hom.: 582 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0937

Gnomad OTH AF: 0.0738

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 12 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0739 AC: 11262 AN: 152310 Hom.: 585 Cov.: 32 AF XY: 0.0743 AC XY: 5530 AN XY: 74468

African (AFR) AF: 0.0140 AC: 584 AN: 41584

American (AMR) AF: 0.0665 AC: 1018 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3470

East Asian (EAS) AF: 0.184 AC: 952 AN: 5184

South Asian (SAS) AF: 0.103 AC: 497 AN: 4826

European-Finnish (FIN) AF: 0.0960 AC: 1018 AN: 10606

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0937 AC: 6377 AN: 68022

Other (OTH) AF: 0.0754 AC: 159 AN: 2110

Alfa AF: 0.0882 Hom.: 835

Bravo AF: 0.0716

Asia WGS AF: 0.140 AC: 486 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.7
DANN	Benign	0.69
PhyloP100		-0.75
PromoterAI		-0.17	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs4379678; hg19: chr1-150780582;