11-88312415-A-G

Position:

chr11-88312415-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I153M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.88 ( 58561 hom., cov: 32)

Exomes 𝑓: 0.86 ( 539197 hom. )

Consequence

CTSC
NM_001814.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.731

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 402572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-88312415-A-G is described in Lovd as [Benign]. Variant chr11-88312415-A-G is described in Lovd as [Likely_benign].

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/exons	MANE	UniProt
CTSC	NM_001814.6 linkuse as main transcript	c.458T>C	p.Ile153Thr	missense_variant	3/7	ENST00000227266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.458T>C	p.Ile153Thr	missense_variant	3/7	1	NM_001814.6	P1	P53634-1

Frequencies

GnomAD3 genomes

AF:

0.876

AC:

133225

AN:

152122

Hom.:

58510

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.884

AC:

222203

AN:

251422

Hom.:

98597

AF XY:

0.883

AC XY:

120048

AN XY:

135882

show subpopulations

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 SAS exome

AF:

0.942

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.:

AF XY:

0.860

AC XY:

625094

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.910

Gnomad4 AMR exome

AF:

0.915

Gnomad4 ASJ exome

AF:

0.757

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.941

Gnomad4 FIN exome

AF:

0.888

Gnomad4 NFE exome

AF:

0.844

Gnomad4 OTH exome

AF:

0.856

GnomAD4 genome

AF:

0.876

AC:

133335

AN:

152240

Hom.:

58561

Cov.:

AF XY:

0.879

AC XY:

65438

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.911

Gnomad4 AMR

AF:

0.888

Gnomad4 ASJ

AF:

0.743

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.943

Gnomad4 FIN

AF:

0.897

Gnomad4 NFE

AF:

0.842

Gnomad4 OTH

AF:

0.858

Alfa

AF:

0.850

Hom.:

103953

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

LINK: link

Submissions by phenotype

not specified

Benign:2

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: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.18

DANN

Benign

0.38

DEOGEN2

Benign

0.13

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0052

LIST_S2

Benign

0.093

MetaRNN

Benign

8.0e-7

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

2.1

REVEL

Benign

0.20

Sift

Benign

0.73

Sift4G

Benign

0.71

Polyphen

0.0

Vest4

0.023

MPC

0.080

ClinPred

0.024

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.065

gMVP

0.51

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