rs3888798

chr11-88294041-T-Cchr11-88294041-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001814.6(CTSC):c.1357A>G(p.Ile453Val) variant causes a missense change. The variant allele was found at a frequency of 0.0486 in 1,613,916 control chromosomes in the GnomAD database, including 2,560 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (292 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2268 hom.)
• Consequence: CTSC NM_001814.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.14

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 Benign. Variant got -18 ACMG points.

• PM1: In a chain Dipeptidyl peptidase 1 light chain (size 68) in uniprot entity CATC_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001814.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.004112333).
• BP6: Variant 11-88294041-T-C is Benign according to our data. Variant chr11-88294041-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 198470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSC	NM_001814.6	c.1357A>G	p.Ile453Val	missense_variant	7/7	ENST00000227266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSC	ENST00000227266.10	c.1357A>G	p.Ile453Val	missense_variant	7/7	1	NM_001814.6	P1

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8833 AN: 152058 Hom.: 294 Cov.: 32

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0723

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0732

Gnomad FIN AF: 0.0912

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0451

GnomAD3 exomes AF: 0.0614 AC: 15419 AN: 251062 Hom.: 631 AF XY: 0.0603 AC XY: 8185 AN XY: 135656

Gnomad AFR exome AF: 0.0699

Gnomad AMR exome AF: 0.0878

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.0896

Gnomad SAS exome AF: 0.0847

Gnomad FIN exome AF: 0.0945

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0476 AC: 69624 AN: 1461740 Hom.: 2268 Cov.: 31 AF XY: 0.0478 AC XY: 34789 AN XY: 727188

Gnomad4 AFR exome AF: 0.0665

Gnomad4 AMR exome AF: 0.0845

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.0830

Gnomad4 FIN exome AF: 0.0915

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0431

GnomAD4 genome AF: 0.0582 AC: 8851 AN: 152176 Hom.: 292 Cov.: 32 AF XY: 0.0609 AC XY: 4527 AN XY: 74392

Gnomad4 AFR AF: 0.0699

Gnomad4 AMR AF: 0.0726

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.0735

Gnomad4 FIN AF: 0.0912

Gnomad4 NFE AF: 0.0416

Gnomad4 OTH AF: 0.0470

Alfa AF: 0.0428 Hom.: 378

Bravo AF: 0.0556

TwinsUK AF: 0.0405 AC: 150

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.0686 AC: 302

ESP6500EA AF: 0.0386 AC: 332

ExAC AF: 0.0615 AC: 7464

Asia WGS AF: 0.0920 AC: 320 AN: 3478

EpiCase AF: 0.0363

EpiControl AF: 0.0317

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: One paper associating variant with aggressive periodontitis - unrelated to patient disease -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Papillon-Lefèvre syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Haim-Munk syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.47	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.015	D
Sift4G	Benign	0.13	T
Polyphen		0.44	B
Vest4		0.17
MPC		0.10
ClinPred		0.030	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.59

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

Other links and lift over

dbSNP: rs3888798; hg19: chr11-88027209; COSMIC: COSV57056940; COSMIC: COSV57056940;