chr11-88337602-C-T

Position:

chr11-88337602-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001814.6(CTSC):c.71G>A(p.Cys24Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000494 in 1,579,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

CTSC
NM_001814.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.887

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:

CTSC (HGNC:):

CTSC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35528278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSC	NM_001814.6 linkuse as main transcript	c.71G>A	p.Cys24Tyr	missense_variant	1/7	ENST00000227266.10	NP_001805.4	P53634-1
CTSC	NM_001114173.3 linkuse as main transcript	c.71G>A	p.Cys24Tyr	missense_variant	1/4		NP_001107645.1	P53634-3
CTSC	NM_148170.5 linkuse as main transcript	c.71G>A	p.Cys24Tyr	missense_variant	1/4		NP_680475.1	P53634-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.71G>A	p.Cys24Tyr	missense_variant	1/7	1	NM_001814.6	ENSP00000227266.4		P53634-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00000521

AC:

AN:

191804

Hom.:

AF XY:

0.00

AC XY:

AN XY:

103004

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000532

AC:

AN:

1427348

Hom.:

Cov.:

AF XY:

0.0000467

AC XY:

AN XY:

706606

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000658

Gnomad4 OTH exome

AF:

0.0000677

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000832

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 24 of the CTSC protein (p.Cys24Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 534587). 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: "Benign"; Align-GVGD: "Not Available"). 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

0.30

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.50

T;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.095

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.25

B;P;.

Vest4

0.28

MutPred

0.60

Loss of catalytic residue at T26 (P = 0.1521);Loss of catalytic residue at T26 (P = 0.1521);Loss of catalytic residue at T26 (P = 0.1521);

MVP

0.68

MPC

0.19

ClinPred

0.51

GERP RS

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.78

gMVP

0.92

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