Variant rs2230061 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000368985.8(CTSS):c.337C>T(p.Arg113Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,613,552 control chromosomes in the GnomAD database, including 109,160 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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. R113Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.34 ( 9315 hom., cov: 32)

Exomes 𝑓: 0.37 ( 99845 hom. )

Consequence

CTSS
ENST00000368985.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.701

Variant links:

Genes affected

CTSS (HGNC:2545): (cathepsin S) The preproprotein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that participates in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The mature protein cleaves the invariant chain of MHC class II molecules in endolysosomal compartments and enables the formation of antigen-MHC class II complexes and the proper display of extracellular antigenic peptides by MHC-II. The mature protein also functions as an elastase over a broad pH range. When secreted from cells, this protein can remodel components of the extracellular matrix such as elastin, collagen, and fibronectin. This gene is implicated in the pathology of many inflammatory and autoimmune diseases and, given its elastase activity, plays a significant role in some pulmonary diseases. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2020]

CTSS links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.346767E-4).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSS	NM_004079.5 linkuse as main transcript	c.337C>T	p.Arg113Trp	missense_variant	4/8	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2 linkuse as main transcript	c.249+2795C>T		intron_variant			NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8 linkuse as main transcript	c.337C>T	p.Arg113Trp	missense_variant	4/8	1	NM_004079.5	ENSP00000357981	P1	P25774-1

Frequencies

GnomAD3 genomes

AF:

0.344

AC:

52322

AN:

151878

Hom.:

9308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.275

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.433

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.530

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.397

Gnomad NFE

AF:

0.356

Gnomad OTH

AF:

0.348

GnomAD3 exomes

AF:

0.377

AC:

94801

AN:

251262

Hom.:

18485

AF XY:

0.386

AC XY:

52458

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.401

Gnomad ASJ exome

AF:

0.426

Gnomad EAS exome

AF:

0.335

Gnomad SAS exome

AF:

0.521

Gnomad FIN exome

AF:

0.350

Gnomad NFE exome

AF:

0.354

Gnomad OTH exome

AF:

0.376

GnomAD4 exome

AF:

0.367

AC:

535683

AN:

1461556

Hom.:

99845

Cov.:

AF XY:

0.371

AC XY:

270045

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.281

Gnomad4 AMR exome

AF:

0.397

Gnomad4 ASJ exome

AF:

0.428

Gnomad4 EAS exome

AF:

0.363

Gnomad4 SAS exome

AF:

0.520

Gnomad4 FIN exome

AF:

0.351

Gnomad4 NFE exome

AF:

0.355

Gnomad4 OTH exome

AF:

0.375

GnomAD4 genome

AF:

0.344

AC:

52345

AN:

151996

Hom.:

9315

Cov.:

AF XY:

0.350

AC XY:

25966

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.274

Gnomad4 AMR

AF:

0.405

Gnomad4 ASJ

AF:

0.433

Gnomad4 EAS

AF:

0.355

Gnomad4 SAS

AF:

0.529

Gnomad4 FIN

AF:

0.345

Gnomad4 NFE

AF:

0.356

Gnomad4 OTH

AF:

0.352

Alfa

AF:

0.358

Hom.:

17564

Bravo

AF:

0.339

TwinsUK

AF:

0.353

AC:

1309

ALSPAC

AF:

0.364

AC:

1402

ESP6500AA

AF:

0.279

AC:

1229

ESP6500EA

AF:

0.355

AC:

3052

ExAC

AF:

0.376

AC:

45695

Asia WGS

AF:

0.382

AC:

1326

AN:

3478

EpiCase

AF:

0.359

EpiControl

AF:

0.366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.29

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.38

MetaRNN

Benign

0.00013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.88

REVEL

Benign

0.055

Sift

Benign

0.11

Sift4G

Uncertain

0.045

Polyphen

0.90

Vest4

0.052

MPC

0.81

ClinPred

0.014

GERP RS

1.2

Varity_R

0.17

gMVP

0.52

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over