rs4379678

Positions:

• chr1-150808106-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSK	NM_000396.4	c.-2+108A>G		intron_variant		ENST00000271651.8	NP_000387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSK	ENST00000271651.8	c.-2+108A>G		intron_variant		1	NM_000396.4	ENSP00000271651	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0665

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0960

Gnomad4 NFE AF: 0.0937

Gnomad4 OTH AF: 0.0754

Alfa AF: 0.0924 Hom.: 671

Bravo AF: 0.0716

Asia WGS AF: 0.140 AC: 486 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.7
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs4379678; hg19: chr1-150780582;