8-11853379-G-C

Position:

chr8-11853379-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000353047.11(CTSB):c.76C>G(p.Leu26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,611,564 control chromosomes in the GnomAD database, including 119,157 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L26P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.37 ( 10433 hom., cov: 27)

Exomes 𝑓: 0.38 ( 108724 hom. )

Consequence

CTSB
ENST00000353047.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.54

Variant links:

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]

CTSB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038253367).

BP6

Variant 8-11853379-G-C is Benign according to our data. Variant chr8-11853379-G-C is described in ClinVar as [Benign]. Clinvar id is 1168281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSB	NM_001908.5 linkuse as main transcript	c.76C>G	p.Leu26Val	missense_variant	2/10	ENST00000353047.11	NP_001899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSB	ENST00000353047.11 linkuse as main transcript	c.76C>G	p.Leu26Val	missense_variant	2/10	1	NM_001908.5	ENSP00000345672	P3

Frequencies

GnomAD3 genomes

AF:

0.371

AC:

55729

AN:

150304

Hom.:

10429

Cov.:

show subpopulations

Gnomad AFR

AF:

0.329

Gnomad AMI

AF:

0.460

Gnomad AMR

AF:

0.368

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.504

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.416

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.383

Gnomad OTH

AF:

0.373

GnomAD3 exomes

AF:

0.378

AC:

94999

AN:

251104

Hom.:

18339

AF XY:

0.379

AC XY:

51438

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.329

Gnomad AMR exome

AF:

0.351

Gnomad ASJ exome

AF:

0.284

Gnomad EAS exome

AF:

0.503

Gnomad SAS exome

AF:

0.357

Gnomad FIN exome

AF:

0.402

Gnomad NFE exome

AF:

0.383

Gnomad OTH exome

AF:

0.382

GnomAD4 exome

AF:

0.384

AC:

560911

AN:

1461142

Hom.:

108724

Cov.:

AF XY:

0.383

AC XY:

278093

AN XY:

726864

show subpopulations

Gnomad4 AFR exome

AF:

0.328

Gnomad4 AMR exome

AF:

0.354

Gnomad4 ASJ exome

AF:

0.290

Gnomad4 EAS exome

AF:

0.501

Gnomad4 SAS exome

AF:

0.355

Gnomad4 FIN exome

AF:

0.392

Gnomad4 NFE exome

AF:

0.387

Gnomad4 OTH exome

AF:

0.385

GnomAD4 genome

AF:

0.371

AC:

55766

AN:

150422

Hom.:

10433

Cov.:

AF XY:

0.371

AC XY:

27219

AN XY:

73312

show subpopulations

Gnomad4 AFR

AF:

0.329

Gnomad4 AMR

AF:

0.368

Gnomad4 ASJ

AF:

0.299

Gnomad4 EAS

AF:

0.505

Gnomad4 SAS

AF:

0.361

Gnomad4 FIN

AF:

0.416

Gnomad4 NFE

AF:

0.383

Gnomad4 OTH

AF:

0.375

Alfa

AF:

0.366

Hom.:

6740

Bravo

AF:

0.369

TwinsUK

AF:

0.387

AC:

1436

ALSPAC

AF:

0.409

AC:

1576

ESP6500AA

AF:

0.338

AC:

1491

ESP6500EA

AF:

0.375

AC:

3222

ExAC

AF:

0.381

AC:

46185

EpiCase

AF:

0.381

EpiControl

AF:

0.387

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CTSB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T;T;T;T;T;T;T;T;.;.;T;T;.;.;.;T;T;T;T;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.68

.;.;.;.;.;.;T;T;T;T;T;.;T;T;T;T;T;.;T;T;T;T

MetaRNN

Benign

0.0038

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

4.0

H;H;H;H;H;H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.00021

P;P;P;P;P;P;P;P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;D;D;D;D;D;D;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.012

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T;T;D;T;.

Sift4G

Uncertain

0.0090

D;D;D;D;D;D;D;D;D;D;.;.;.;D;.;.;D;.;.;.;.;.

Polyphen

0.010

B;B;B;B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.23

ClinPred

0.055

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over