11-88294041-T-C

Variant names:

Variant summary

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

The NM_001814.6(CTSC):c.1357A>G(p.Ile453Val) variant causes a missense change. The variant allele was found at a frequency of 0.0486 in 1,613,916 control chromosomes in the GnomAD database, including 2,560 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 292 hom., cov: 32)

Exomes 𝑓: 0.048 ( 2268 hom. )

Consequence

CTSC
NM_001814.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.14

Variant links:

Genes affected

CTSC (HGNC:2528): (cathepsin C) This gene encodes a member of the peptidase C1 family and lysosomal cysteine proteinase that appears to be a central coordinator for activation of many serine proteinases in cells of the immune system. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate heavy and light chains that form a disulfide-linked dimer. A portion of the propeptide acts as an intramolecular chaperone for the folding and stabilization of the mature enzyme. This enzyme requires chloride ions for activity and can degrade glucagon. Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre syndrome, an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis. [provided by RefSeq, Nov 2015]

CTSC 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=0.004112333).

BP6

Variant 11-88294041-T-C is Benign according to our data. Variant chr11-88294041-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 198470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6 link	c.1357A>G	p.Ile453Val	missense_variant	Exon 7 of 7	ENST00000227266.10	NP_001805.4	P53634-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10 link	c.1357A>G	p.Ile453Val	missense_variant	Exon 7 of 7	1	NM_001814.6	ENSP00000227266.4		P53634-1

Frequencies

GnomAD3 genomes

AF:

0.0581

AC:

8833

AN:

152058

Hom.:

294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0699

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0723

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.0732

Gnomad FIN

AF:

0.0912

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0416

Gnomad OTH

AF:

0.0451

GnomAD3 exomes

AF:

0.0614

AC:

15419

AN:

251062

Hom.:

631

AF XY:

0.0603

AC XY:

8185

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.0699

Gnomad AMR exome

AF:

0.0878

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.0896

Gnomad SAS exome

AF:

0.0847

Gnomad FIN exome

AF:

0.0945

Gnomad NFE exome

AF:

0.0407

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0476

AC:

69624

AN:

1461740

Hom.:

2268

Cov.:

AF XY:

0.0478

AC XY:

34789

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0665

Gnomad4 AMR exome

AF:

0.0845

Gnomad4 ASJ exome

AF:

0.00708

Gnomad4 EAS exome

AF:

0.129

Gnomad4 SAS exome

AF:

0.0830

Gnomad4 FIN exome

AF:

0.0915

Gnomad4 NFE exome

AF:

0.0391

Gnomad4 OTH exome

AF:

0.0431

GnomAD4 genome

AF:

0.0582

AC:

8851

AN:

152176

Hom.:

292

Cov.:

AF XY:

0.0609

AC XY:

4527

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0699

Gnomad4 AMR

AF:

0.0726

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.106

Gnomad4 SAS

AF:

0.0735

Gnomad4 FIN

AF:

0.0912

Gnomad4 NFE

AF:

0.0416

Gnomad4 OTH

AF:

0.0470

Alfa

AF:

0.0428

Hom.:

378

Bravo

AF:

0.0556

TwinsUK

AF:

0.0405

AC:

150

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.0686

AC:

302

ESP6500EA

AF:

0.0386

AC:

332

ExAC

AF:

0.0615

AC:

7464

Asia WGS

AF:

0.0920

AC:

320

AN:

3478

EpiCase

AF:

0.0363

EpiControl

AF:

0.0317

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Sep 11, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: One paper associating variant with aggressive periodontitis - unrelated to patient disease -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Papillon-Lefèvre syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Haim-Munk syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-0.47

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.68

REVEL

Uncertain

0.36

Sift

Uncertain

0.015

Sift4G

Benign

0.13

Polyphen

0.44

Vest4

0.17

MPC

0.10

ClinPred

0.030

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.59

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