rs104894206

chr11-88309176-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001814.6(CTSC):c.628C>T(p.Arg210Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,548 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CTSC NM_001814.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-88309176-G-A is Pathogenic according to our data. Variant chr11-88309176-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7289.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSC	NM_001814.6	c.628C>T	p.Arg210Ter	stop_gained	4/7	ENST00000227266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSC	ENST00000227266.10	c.628C>T	p.Arg210Ter	stop_gained	4/7	1	NM_001814.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461548 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727104

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Papillon-Lefèvre syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1999

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7289). This premature translational stop signal has been observed in individuals with Papillon-Lefèvre syndrome (PMID: 10581027, 28242153). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg210*) in the CTSC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTSC are known to be pathogenic (PMID: 10662808, 11106356, 11886537). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	35
Dann	Uncertain	0.98
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.060	N
MutationTaster	Benign	1.0	A
Vest4		0.86
GERP RS		-0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs104894206; hg19: chr11-88042344;