11-88337557-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W39C) has been classified as Uncertain significance.

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:2U:1

Conservation

PhyloP100: 6.65

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Papillon-Lefevre disease
Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Haim-Munk syndrome
Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
ectodermal dysplasia syndrome
Inheritance: AR Classification: STRONG Submitted by: Illumina
periodontitis, aggressive 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CTSC links:

ENSG00000288018 (HGNC:):

ENSG00000288018 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 7296.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001814.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTSC	NM_001814.6	MANE Select	c.116G>C	p.Trp39Ser	missense	Exon 1 of 7	NP_001805.4
CTSC	NM_001114173.3		c.116G>C	p.Trp39Ser	missense	Exon 1 of 4	NP_001107645.1
CTSC	NM_148170.5		c.116G>C	p.Trp39Ser	missense	Exon 1 of 4	NP_680475.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTSC	ENST00000227266.10	TSL:1 MANE Select	c.116G>C	p.Trp39Ser	missense	Exon 1 of 7	ENSP00000227266.4
CTSC	ENST00000529974.2	TSL:1	c.116G>C	p.Trp39Ser	missense	Exon 1 of 4	ENSP00000433539.1
CTSC	ENST00000524463.6	TSL:1	c.116G>C	p.Trp39Ser	missense	Exon 1 of 4	ENSP00000432541.1

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

GnomAD2 exomes

AF:

0.0000107

AC:

AN:

187450

AF XY:

0.00000994

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 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

African (AFR)

AF:

0.00

AC:

AN:

32588

American (AMR)

AF:

0.0000251

AC:

AN:

39834

Ashkenazi Jewish (ASJ)

AF:

0.0000392

AC:

AN:

25498

East Asian (EAS)

AF:

0.00

AC:

AN:

37582

South Asian (SAS)

AF:

0.00

AC:

AN:

81334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092340

Other (OTH)

AF:

0.00

AC:

AN:

58968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Papillon-Lefèvre syndrome

Pathogenic:1

Feb 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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

Pathogenic:1

Jan 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

CTSC-related disorder

Uncertain:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CTSC c.116G>C variant is predicted to result in the amino acid substitution p.Trp39Ser. This variant has been reported in the homozygous state in four individuals with Papillon-Lefevre syndrome from the same family (Family 1, Nakano et al. 2001. PubMed ID: 11180012). This variant is reported in 0.011% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Of note, another variant impacting the same amino acid [c.117G>T (Trp39Cys)] has also been reported in the homozygous state in an individual with Papillon-Lefevre syndrome (Tekin et al. 2016. PubMed ID: 27062382). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

PhyloP100

6.7

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-13

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.86

MutPred

0.98

Gain of disorder (P = 0.0037)

MVP

0.99

MPC

0.50

ClinPred

1.0

GERP RS

5.0

PromoterAI

0.072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.98

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over