8-11853379-G-T

Position:

chr8-11853379-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001317237.2(CTSB):c.-178C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,611,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CTSB
NM_001317237.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

CTSB (HGNC:):

CTSB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSB	NM_001908.5 linkuse as main transcript	c.76C>A	p.Leu26Met	missense_variant	2/10	ENST00000353047.11	NP_001899.1	P07858A0A024R374

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSB	ENST00000353047.11 linkuse as main transcript	c.76C>A	p.Leu26Met	missense_variant	2/10	1	NM_001908.5	ENSP00000345672.5		P07858

Frequencies

GnomAD3 genomes

AF:

0.0000665

AC:

AN:

150460

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000599

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000488

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251104

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000664

AC:

AN:

150578

Hom.:

Cov.:

AF XY:

0.0000681

AC XY:

AN XY:

73404

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000598

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000483

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with CTSB-related conditions. This variant is present in population databases (rs12338, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 26 of the CTSB protein (p.Leu26Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

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

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.71

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

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.62

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.066

MutationAssessor

Pathogenic

3.5

M;M;M;M;M;M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.011

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

Sift4G

Uncertain

0.018

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

Polyphen

0.97

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

Vest4

0.42

MutPred

0.75

Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);Gain of disorder (P = 0.0961);

MVP

0.54

ClinPred

0.63

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.53

gMVP

0.68

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