11-88312415-A-G

Variant names:

• chr11-88312415-A-G
• rs217086
• NM_001814.6:c.458T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001814.6(CTSC):​c.458T>C​(p.Ile153Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 1,613,912 control chromosomes in the GnomAD database, including 597,758 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58561 hom., cov: 32)
  • Exomes 𝑓: 0.86 (539197 hom.)
• Consequence: CTSC NM_001814.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.731
• Publications: 52 publications found

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 Gene-Disease associations (from GenCC):

• Papillon-Lefevre disease

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Haim-Munk syndrome

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• ectodermal dysplasia syndrome

  Inheritance: AR Classification: STRONG Submitted by: Illumina
• periodontitis, aggressive 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.991115E-7).
• BP6: Variant 11-88312415-A-G is Benign according to our data. Variant chr11-88312415-A-G is described in ClinVar as Benign. ClinVar VariationId is 402572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6	c.458T>C	p.Ile153Thr	missense_variant	Exon 3 of 7	ENST00000227266.10	NP_001805.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10	c.458T>C	p.Ile153Thr	missense_variant	Exon 3 of 7	1	NM_001814.6	ENSP00000227266.4

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133225 AN: 152122 Hom.: 58510 Cov.: 32

Gnomad AFR AF: 0.911

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.897

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.857

GnomAD2 exomes AF: 0.884 AC: 222203 AN: 251422 AF XY: 0.883

Gnomad AFR exome AF: 0.914

Gnomad AMR exome AF: 0.917

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.889

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.864

GnomAD4 exome AF: 0.858 AC: 1253960 AN: 1461672 Hom.: 539197 Cov.: 51 AF XY: 0.860 AC XY: 625094 AN XY: 727150

African (AFR) AF: 0.910 AC: 30458 AN: 33478

American (AMR) AF: 0.915 AC: 40924 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 19772 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39684 AN: 39698

South Asian (SAS) AF: 0.941 AC: 81139 AN: 86250

European-Finnish (FIN) AF: 0.888 AC: 47432 AN: 53418

Middle Eastern (MID) AF: 0.832 AC: 4797 AN: 5768

European-Non Finnish (NFE) AF: 0.844 AC: 938091 AN: 1111816

Other (OTH) AF: 0.856 AC: 51663 AN: 60386

GnomAD4 genome AF: 0.876 AC: 133335 AN: 152240 Hom.: 58561 Cov.: 32 AF XY: 0.879 AC XY: 65438 AN XY: 74436

African (AFR) AF: 0.911 AC: 37856 AN: 41558

American (AMR) AF: 0.888 AC: 13571 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2578 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5169 AN: 5176

South Asian (SAS) AF: 0.943 AC: 4552 AN: 4828

European-Finnish (FIN) AF: 0.897 AC: 9514 AN: 10604

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.842 AC: 57248 AN: 68004

Other (OTH) AF: 0.858 AC: 1814 AN: 2114

Alfa AF: 0.853 Hom.: 140905

Bravo AF: 0.877

TwinsUK AF: 0.838 AC: 3108

ALSPAC AF: 0.851 AC: 3280

ESP6500AA AF: 0.911 AC: 4012

ESP6500EA AF: 0.840 AC: 7221

ExAC AF: 0.886 AC: 107579

Asia WGS AF: 0.968 AC: 3362 AN: 3476

EpiCase AF: 0.838

EpiControl AF: 0.840

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.18
DANN	Benign	0.38
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.093	T
MetaRNN	Benign	8.0e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.3	N
PhyloP100		-0.73
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.20
Sift	Benign	0.73	T
Sift4G	Benign	0.71	T
Vest4		0.023
ClinPred		0.024	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.51
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs217086; hg19: chr11-88045583; COSMIC: COSV57060752;