rs104894210

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_001814.6(CTSC):c.116G>C(p.Trp39Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000019 in 1,576,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CTSC
NM_001814.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.65

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 Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 11-88337557-C-G is Pathogenic according to our data. Variant chr11-88337557-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7296.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null. Variant chr11-88337557-C-G is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CTSC	NM_001814.6 linkuse as main transcript	c.116G>C	p.Trp39Ser	missense_variant	1/7	ENST00000227266.10
CTSC	NM_001114173.3 linkuse as main transcript	c.116G>C	p.Trp39Ser	missense_variant	1/4
CTSC	NM_148170.5 linkuse as main transcript	c.116G>C	p.Trp39Ser	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.116G>C	p.Trp39Ser	missense_variant	1/7	1	NM_001814.6	P1	P53634-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

GnomAD3 exomes

AF:

0.0000107

AC:

AN:

187450

Hom.:

AF XY:

0.00000994

AC XY:

AN XY:

100562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000348

Gnomad ASJ exome

AF:

0.000111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1424558

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705038

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000251

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Papillon-Lefèvre syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2001

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 39 of the CTSC protein (p.Trp39Ser). This variant is present in population databases (rs104894210, gnomAD 0.01%). This missense change has been observed in individual(s) with Papillon-Lefevre syndrome (PMID: 11180012). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7296). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Trp39 amino acid residue in CTSC. Other variant(s) that disrupt this residue have been observed in individuals with CTSC-related conditions (PMID: 27062382), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.58

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;M;M

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-13

D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.040

D;D;D

Polyphen

1.0

D;P;.

Vest4

0.86

MutPred

0.98

Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);

MVP

0.99

MPC

0.50

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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