8-11869308-A-G

Position:

• chr8-11869308-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000534382.6(CTSB):​c.-457T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 149,306 control chromosomes in the GnomAD database, including 7,936 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 0.33 (7929 hom., cov: 27)
  • Exomes 𝑓: 0.35 (7 hom.)
• Consequence: CTSB ENST00000534382.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339

Genes affected

CTSB (HGNC:2527): (cathepsin B) This gene encodes a member of the C1 family of peptidases. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the cathepsin B light and heavy chains, which can dimerize to form the double chain form of the enzyme. This enzyme is a lysosomal cysteine protease with both endopeptidase and exopeptidase activity that may play a role in protein turnover. It is also known as amyloid precursor protein secretase and is involved in the proteolytic processing of amyloid precursor protein (APP). Incomplete proteolytic processing of APP has been suggested to be a causative factor in Alzheimer's disease, the most common cause of dementia. Overexpression of the encoded protein has been associated with esophageal adenocarcinoma and other tumors. Both Cathepsin B and Cathepsin L are involved in the cleavage of the spike protein from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon its entry to the human host cell. Multiple pseudogenes of this gene have been identified. [provided by RefSeq, Sep 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSB	ENST00000534382.6	c.-457T>C		5_prime_UTR_variant	1/10	4		ENSP00000435260	P3
CTSB	ENST00000677671.1	c.-412T>C		5_prime_UTR_variant	1/10			ENSP00000503578	P3

Frequencies

GnomAD3 genomes AF: 0.325 AC: 48500 AN: 149110 Hom.: 7930 Cov.: 27

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.281

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.312

GnomAD4 exome AF: 0.347 AC: 34 AN: 98 Hom.: 7 Cov.: 0 AF XY: 0.368 AC XY: 28 AN XY: 76

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.350

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.325 AC: 48532 AN: 149208 Hom.: 7929 Cov.: 27 AF XY: 0.327 AC XY: 23764 AN XY: 72686

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.305

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.314

Alfa AF: 0.313 Hom.: 9515

Bravo AF: 0.318

Asia WGS AF: 0.413 AC: 1436 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.5
DANN	Benign	0.56

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1296023; hg19: chr8-11726817;