rs13332

Positions:

• chr8-11849072-T-C
• chr8-11849072-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001908.5(CTSB):​c.420A>G​(p.Thr140=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,612,684 control chromosomes in the GnomAD database, including 2,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T140T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.072 (796 hom., cov: 33)
  • Exomes 𝑓: 0.028 (1218 hom.)
• Consequence: CTSB NM_001908.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.26

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 8-11849072-T-C is Benign according to our data. Variant chr8-11849072-T-C is described in ClinVar as [Benign]. Clinvar id is 1164778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSB	NM_001908.5	c.420A>G	p.Thr140=	synonymous_variant	5/10	ENST00000353047.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSB	ENST00000353047.11	c.420A>G	p.Thr140=	synonymous_variant	5/10	1	NM_001908.5	P3

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10934 AN: 152034 Hom.: 791 Cov.: 33

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.0619

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0258

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0353 AC: 8821 AN: 249570 Hom.: 424 AF XY: 0.0321 AC XY: 4339 AN XY: 135114

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0592

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0232

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0283 AC: 41309 AN: 1460532 Hom.: 1218 Cov.: 38 AF XY: 0.0278 AC XY: 20219 AN XY: 726588

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0563

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.0159

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0374

GnomAD4 genome AF: 0.0721 AC: 10972 AN: 152152 Hom.: 796 Cov.: 33 AF XY: 0.0708 AC XY: 5265 AN XY: 74370

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0435

Gnomad4 ASJ AF: 0.0619

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0262

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0261

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0346 Hom.: 2418

EpiCase AF: 0.0292

EpiControl AF: 0.0290

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

CTSB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.5
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs13332; hg19: chr8-11706581;