rs2230081

Positions:

chr11-88296197-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001814.6(CTSC):c.825C>T(p.Thr275=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,954 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 112 hom. )

Consequence

CTSC
NM_001814.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.07

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 11-88296197-G-A is Benign according to our data. Variant chr11-88296197-G-A is described in ClinVar as [Benign]. Clinvar id is 466229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.08 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00763 (1162/152258) while in subpopulation NFE AF= 0.0121 (820/68034). AF 95% confidence interval is 0.0114. There are 7 homozygotes in gnomad4. There are 554 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSC	NM_001814.6 linkuse as main transcript	c.825C>T	p.Thr275=	synonymous_variant	6/7	ENST00000227266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.825C>T	p.Thr275=	synonymous_variant	6/7	1	NM_001814.6	P1	P53634-1

Frequencies

GnomAD3 genomes

AF:

0.00764

AC:

1162

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00903

AC:

2271

AN:

251448

Hom.:

AF XY:

0.00881

AC XY:

1197

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00645

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.00880

GnomAD4 exome

AF:

0.0106

AC:

15462

AN:

1461696

Hom.:

112

Cov.:

AF XY:

0.0103

AC XY:

7484

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00297

Gnomad4 ASJ exome

AF:

0.00589

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00313

Gnomad4 FIN exome

AF:

0.0160

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00921

GnomAD4 genome

AF:

0.00763

AC:

1162

AN:

152258

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

554

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0148

Gnomad4 NFE

AF:

0.0121

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.0100

Hom.:

Bravo

AF:

0.00683

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0102

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Papillon-Lefèvre syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

CTSC: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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