11-88335088-GAAAA-GAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001814.6(CTSC):c.173-8_173-7delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,219,114 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0000093 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00099 ( 0 hom. )

Consequence

CTSC
NM_001814.6 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.633

Publications

1 publications found

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 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)

CTSC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 11-88335088-GAA-G is Benign according to our data. Variant chr11-88335088-GAA-G is described in ClinVar as [Benign]. Clinvar id is 2930306.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6 link	c.173-8_173-7delTT	splice_region_variant, intron_variant	Intron 1 of 6	ENST00000227266.10	NP_001805.4	P53634-1
CTSC	NM_001114173.3 link	c.173-8_173-7delTT	splice_region_variant, intron_variant	Intron 1 of 3		NP_001107645.1	P53634-3
CTSC	NM_148170.5 link	c.173-8_173-7delTT	splice_region_variant, intron_variant	Intron 1 of 3		NP_680475.1	P53634-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10 link	c.173-8_173-7delTT		splice_region_variant, intron_variant	Intron 1 of 6	1	NM_001814.6	ENSP00000227266.4		P53634-1

Frequencies

GnomAD3 genomes

AF:

0.00000925

AC:

AN:

108094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000154

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00136

AC:

181

AN:

132778

AF XY:

0.00124

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.00204

Gnomad ASJ exome

AF:

0.000805

Gnomad EAS exome

AF:

0.000964

Gnomad FIN exome

AF:

0.00235

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.000990

AC:

1100

AN:

1111020

Hom.:

AF XY:

0.000881

AC XY:

494

AN XY:

560576

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00156

AC:

AN:

25696

American (AMR)

AF:

0.00131

AC:

AN:

35870

Ashkenazi Jewish (ASJ)

AF:

0.000277

AC:

AN:

21698

East Asian (EAS)

AF:

0.00114

AC:

AN:

34960

South Asian (SAS)

AF:

0.000541

AC:

AN:

72024

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

42626

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00103

AC:

851

AN:

826820

Other (OTH)

AF:

0.000678

AC:

AN:

47190

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.251

Heterozygous variant carriers

153

306

459

612

765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000925

AC:

AN:

108094

Hom.:

Cov.:

AF XY:

0.0000192

AC XY:

AN XY:

52066

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29484

American (AMR)

AF:

0.00

AC:

AN:

10852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2486

East Asian (EAS)

AF:

0.00

AC:

AN:

3774

South Asian (SAS)

AF:

0.00

AC:

AN:

3510

European-Finnish (FIN)

AF:

0.000154

AC:

AN:

6508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

49282

Other (OTH)

AF:

0.00

AC:

AN:

1438

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000474

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jun 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CTSC-related disorder

Benign:1

Jan 08, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism

(source)

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

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11-88335088-GAAAA-GAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over