11-88335088-GAAAA-GAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001814.6(CTSC):c.173-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,037,614 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 29)

Exomes 𝑓: 0.19 ( 1 hom. )

Consequence

CTSC
NM_001814.6 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -0.410

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: Benign. The variant received -9 ACMG points.

BP6

Variant 11-88335088-G-GA is Benign according to our data. Variant chr11-88335088-G-GA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 306431.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00189 (204/108014) while in subpopulation AFR AF = 0.00362 (107/29534). AF 95% confidence interval is 0.00307. There are 2 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6 link	c.173-7dupT	splice_region_variant, intron_variant	Intron 1 of 6	ENST00000227266.10	NP_001805.4	P53634-1
CTSC	NM_001114173.3 link	c.173-7dupT	splice_region_variant, intron_variant	Intron 1 of 3		NP_001107645.1	P53634-3
CTSC	NM_148170.5 link	c.173-7dupT	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.173-7dupT		splice_region_variant, intron_variant	Intron 1 of 6	1	NM_001814.6	ENSP00000227266.4		P53634-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

202

AN:

107974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000554

Gnomad ASJ

AF:

0.000806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000285

Gnomad FIN

AF:

0.00477

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00348

GnomAD2 exomes

AF:

0.136

AC:

17997

AN:

132778

AF XY:

0.133

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.168

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.170

Gnomad FIN exome

AF:

0.0581

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.186

AC:

173299

AN:

929600

Hom.:

Cov.:

AF XY:

0.185

AC XY:

85487

AN XY:

462740

show subpopulations

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

African (AFR)

AF:

0.169

AC:

3711

AN:

21950

American (AMR)

AF:

0.140

AC:

4210

AN:

30096

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

3363

AN:

16678

East Asian (EAS)

AF:

0.150

AC:

4244

AN:

28258

South Asian (SAS)

AF:

0.167

AC:

9141

AN:

54848

European-Finnish (FIN)

AF:

0.120

AC:

4206

AN:

35092

Middle Eastern (MID)

AF:

0.157

AC:

546

AN:

3476

European-Non Finnish (NFE)

AF:

0.195

AC:

136485

AN:

701026

Other (OTH)

AF:

0.194

AC:

7393

AN:

38176

⚠️ 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: 0.275

Heterozygous variant carriers

16735

33471

50206

66942

83677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00189

AC:

204

AN:

108014

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

105

AN XY:

52036

show subpopulations

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

African (AFR)

AF:

0.00362

AC:

107

AN:

29534

American (AMR)

AF:

0.000553

AC:

AN:

10848

Ashkenazi Jewish (ASJ)

AF:

0.000806

AC:

AN:

2482

East Asian (EAS)

AF:

0.000266

AC:

AN:

3762

South Asian (SAS)

AF:

0.000286

AC:

AN:

3496

European-Finnish (FIN)

AF:

0.00477

AC:

AN:

6500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.00104

AC:

AN:

49200

Other (OTH)

AF:

0.00346

AC:

AN:

1444

⚠️ 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: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0603

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Papillon-Lefèvre syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Haim-Munk syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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

PhyloP100

-0.41

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-GAAAAA

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