chr11-88294225-A-C

Variant names:

• chr11-88294225-A-C
• rs17594
• NM_001814.6:c.1173T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001814.6(CTSC):​c.1173T>G​(p.Thr391Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 1,613,914 control chromosomes in the GnomAD database, including 2,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (293 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2346 hom.)
• Consequence: CTSC NM_001814.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.56

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-88294225-A-C is Benign according to our data. Variant chr11-88294225-A-C is described in ClinVar as [Benign]. Clinvar id is 258189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6	c.1173T>G	p.Thr391Thr	synonymous_variant	Exon 7 of 7	ENST00000227266.10	NP_001805.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10	c.1173T>G	p.Thr391Thr	synonymous_variant	Exon 7 of 7	1	NM_001814.6	ENSP00000227266.4

Frequencies

GnomAD3 genomes AF: 0.0583 AC: 8862 AN: 151982 Hom.: 295 Cov.: 32

Gnomad AFR AF: 0.0700

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0719

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0843

Gnomad FIN AF: 0.0917

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0414

Gnomad OTH AF: 0.0436

GnomAD2 exomes AF: 0.0627 AC: 15739 AN: 250872 AF XY: 0.0621

Gnomad AFR exome AF: 0.0699

Gnomad AMR exome AF: 0.0878

Gnomad ASJ exome AF: 0.00706

Gnomad EAS exome AF: 0.0895

Gnomad FIN exome AF: 0.0946

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0461

GnomAD4 exome AF: 0.0482 AC: 70506 AN: 1461814 Hom.: 2346 Cov.: 32 AF XY: 0.0487 AC XY: 35436 AN XY: 727206

Gnomad4 AFR exome AF: 0.0664 AC: 2224 AN: 33480

Gnomad4 AMR exome AF: 0.0845 AC: 3776 AN: 44696

Gnomad4 ASJ exome AF: 0.00708 AC: 185 AN: 26136

Gnomad4 EAS exome AF: 0.129 AC: 5106 AN: 39700

Gnomad4 SAS exome AF: 0.0932 AC: 8042 AN: 86250

Gnomad4 FIN exome AF: 0.0915 AC: 4889 AN: 53420

Gnomad4 NFE exome AF: 0.0391 AC: 43480 AN: 1111968

Gnomad4 Remaining exome AF: 0.0439 AC: 2649 AN: 60396

GnomAD4 genome AF: 0.0584 AC: 8880 AN: 152100 Hom.: 293 Cov.: 32 AF XY: 0.0614 AC XY: 4563 AN XY: 74320

Gnomad4 AFR AF: 0.0700 AC: 0.0700005 AN: 0.0700005

Gnomad4 AMR AF: 0.0722 AC: 0.0722324 AN: 0.0722324

Gnomad4 ASJ AF: 0.00548 AC: 0.0054755 AN: 0.0054755

Gnomad4 EAS AF: 0.105 AC: 0.10462 AN: 0.10462

Gnomad4 SAS AF: 0.0846 AC: 0.0846154 AN: 0.0846154

Gnomad4 FIN AF: 0.0917 AC: 0.0917188 AN: 0.0917188

Gnomad4 NFE AF: 0.0414 AC: 0.0413799 AN: 0.0413799

Gnomad4 OTH AF: 0.0455 AC: 0.0455408 AN: 0.0455408

Alfa AF: 0.0410 Hom.: 249

Bravo AF: 0.0556

Asia WGS AF: 0.102 AC: 352 AN: 3478

EpiCase AF: 0.0365

EpiControl AF: 0.0317

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: Frequency -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Papillon-Lefèvre syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Haim-Munk syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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: rs17594; hg19: chr11-88027393; COSMIC: COSV57056951; COSMIC: COSV57056951;