rs779944464

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001814.6(CTSC):c.299A>G(p.Lys100Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,846 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CTSC
NM_001814.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.47

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CTSC	NM_001814.6 linkuse as main transcript	c.299A>G	p.Lys100Arg	missense_variant	2/7	ENST00000227266.10
CTSC	NM_001114173.3 linkuse as main transcript	c.299A>G	p.Lys100Arg	missense_variant	2/4
CTSC	NM_148170.5 linkuse as main transcript	c.299A>G	p.Lys100Arg	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.299A>G	p.Lys100Arg	missense_variant	2/7	1	NM_001814.6	P1	P53634-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251340

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460798

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 100 of the CTSC protein (p.Lys100Arg). This variant is present in population databases (rs779944464, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CTSC-related conditions. ClinVar contains an entry for this variant (Variation ID: 466227). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.9

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.2

N;N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.069

T;T;T

Sift4G

Benign

0.13

T;D;D

Polyphen

0.97

D;D;.

Vest4

0.84

MutPred

0.73

Loss of ubiquitination at K100 (P = 0.0224);Loss of ubiquitination at K100 (P = 0.0224);Loss of ubiquitination at K100 (P = 0.0224);

MVP

0.90

MPC

0.31

ClinPred

0.91

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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