rs17594

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001814.6(CTSC):c.1173T>G(p.Thr391=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 1,613,914 control chromosomes in the GnomAD database, including 2,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 293 hom., cov: 32)

Exomes 𝑓: 0.048 ( 2346 hom. )

Consequence

CTSC
NM_001814.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.56

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-88294225-A-C is Benign according to our data. Variant chr11-88294225-A-C is described in ClinVar as [Benign]. Clinvar id is 258189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSC	NM_001814.6 linkuse as main transcript	c.1173T>G	p.Thr391=	synonymous_variant	7/7	ENST00000227266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.1173T>G	p.Thr391=	synonymous_variant	7/7	1	NM_001814.6	P1	P53634-1

Frequencies

GnomAD3 genomes

AF:

0.0583

AC:

8862

AN:

151982

Hom.:

295

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0700

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0719

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.105

Gnomad SAS

AF:

0.0843

Gnomad FIN

AF:

0.0917

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0414

Gnomad OTH

AF:

0.0436

GnomAD3 exomes

AF:

0.0627

AC:

15739

AN:

250872

Hom.:

665

AF XY:

0.0621

AC XY:

8414

AN XY:

135552

show subpopulations

Gnomad AFR exome

AF:

0.0699

Gnomad AMR exome

AF:

0.0878

Gnomad ASJ exome

AF:

0.00706

Gnomad EAS exome

AF:

0.0895

Gnomad SAS exome

AF:

0.0954

Gnomad FIN exome

AF:

0.0946

Gnomad NFE exome

AF:

0.0406

Gnomad OTH exome

AF:

0.0461

GnomAD4 exome

AF:

0.0482

AC:

70506

AN:

1461814

Hom.:

2346

Cov.:

AF XY:

0.0487

AC XY:

35436

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0664

Gnomad4 AMR exome

AF:

0.0845

Gnomad4 ASJ exome

AF:

0.00708

Gnomad4 EAS exome

AF:

0.129

Gnomad4 SAS exome

AF:

0.0932

Gnomad4 FIN exome

AF:

0.0915

Gnomad4 NFE exome

AF:

0.0391

Gnomad4 OTH exome

AF:

0.0439

GnomAD4 genome

AF:

0.0584

AC:

8880

AN:

152100

Hom.:

293

Cov.:

AF XY:

0.0614

AC XY:

4563

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0700

Gnomad4 AMR

AF:

0.0722

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.105

Gnomad4 SAS

AF:

0.0846

Gnomad4 FIN

AF:

0.0917

Gnomad4 NFE

AF:

0.0414

Gnomad4 OTH

AF:

0.0455

Alfa

AF:

0.0388

Hom.:

183

Bravo

AF:

0.0556

Asia WGS

AF:

0.102

AC:

352

AN:

3478

EpiCase

AF:

0.0365

EpiControl

AF:

0.0317

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2017	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. -

Papillon-Lefèvre syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Haim-Munk syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

Cadd

Benign

2.1

Dann

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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