Variant rs41271951 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004079.5(CTSS):c.20T>C(p.Val7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 1,613,994 control chromosomes in the GnomAD database, including 4,371 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.050 ( 256 hom., cov: 31)

Exomes 𝑓: 0.071 ( 4115 hom. )

Consequence

CTSS
NM_004079.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0450

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003063053).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSS	NM_004079.5 linkuse as main transcript	c.20T>C	p.Val7Ala	missense_variant	2/8	ENST00000368985.8
CTSS	NM_001199739.2 linkuse as main transcript	c.20T>C	p.Val7Ala	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSS	ENST00000368985.8 linkuse as main transcript	c.20T>C	p.Val7Ala	missense_variant	2/8	1	NM_004079.5	P1	P25774-1

Frequencies

GnomAD3 genomes

AF:

0.0505

AC:

7687

AN:

152170

Hom.:

256

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0413

Gnomad ASJ

AF:

0.0551

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.0743

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0775

Gnomad OTH

AF:

0.0506

GnomAD3 exomes

AF:

0.0506

AC:

12704

AN:

251284

Hom.:

416

AF XY:

0.0505

AC XY:

6862

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.0264

Gnomad ASJ exome

AF:

0.0588

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0153

Gnomad FIN exome

AF:

0.0710

Gnomad NFE exome

AF:

0.0758

Gnomad OTH exome

AF:

0.0611

GnomAD4 exome

AF:

0.0705

AC:

103085

AN:

1461706

Hom.:

4115

Cov.:

AF XY:

0.0688

AC XY:

50026

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.0113

Gnomad4 AMR exome

AF:

0.0285

Gnomad4 ASJ exome

AF:

0.0593

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0158

Gnomad4 FIN exome

AF:

0.0664

Gnomad4 NFE exome

AF:

0.0816

Gnomad4 OTH exome

AF:

0.0667

GnomAD4 genome

AF:

0.0505

AC:

7686

AN:

152288

Hom.:

256

Cov.:

AF XY:

0.0490

AC XY:

3646

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0141

Gnomad4 AMR

AF:

0.0412

Gnomad4 ASJ

AF:

0.0551

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0126

Gnomad4 FIN

AF:

0.0743

Gnomad4 NFE

AF:

0.0775

Gnomad4 OTH

AF:

0.0501

Alfa

AF:

0.0721

Hom.:

705

Bravo

AF:

0.0472

TwinsUK

AF:

0.0747

AC:

277

ALSPAC

AF:

0.0784

AC:

302

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.0815

AC:

701

ExAC

AF:

0.0502

AC:

6091

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0765

EpiControl

AF:

0.0717

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.57

Cadd

Benign

3.3

Dann

Benign

0.70

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.39

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.64

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.24

Sift

Benign

0.42

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0

B;.

Vest4

0.037

MPC

0.66

ClinPred

0.0024

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.035

gMVP

0.53

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