11-88335088-GAAA-GAAAA

Position:

chr11-88335088-GAAA-GAAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

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

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:

CTSC (HGNC:):

CTSC links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 submissions are: {Uncertain_significance=2, Benign=1}.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CTSC	NM_001814.6 linkuse as main transcript	c.173-7dupT	splice_region_variant, intron_variant	ENST00000227266.10	NP_001805.4	P53634-1
CTSC	NM_001114173.3 linkuse as main transcript	c.173-7dupT	splice_region_variant, intron_variant		NP_001107645.1	P53634-3
CTSC	NM_148170.5 linkuse as main transcript	c.173-7dupT	splice_region_variant, intron_variant		NP_680475.1	P53634-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.173-7dupT		splice_region_variant, intron_variant		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

GnomAD4 exome

AF:

0.186

AC:

173299

AN:

929600

Hom.:

Cov.:

AF XY:

0.185

AC XY:

85487

AN XY:

462740

show subpopulations

Gnomad4 AFR exome

AF:

0.169

Gnomad4 AMR exome

AF:

0.140

Gnomad4 ASJ exome

AF:

0.202

Gnomad4 EAS exome

AF:

0.150

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.120

Gnomad4 NFE exome

AF:

0.195

Gnomad4 OTH exome

AF:

0.194

GnomAD4 genome

AF:

0.00189

AC:

204

AN:

108014

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

105

AN XY:

52036

show subpopulations

Gnomad4 AFR

AF:

0.00362

Gnomad4 AMR

AF:

0.000553

Gnomad4 ASJ

AF:

0.000806

Gnomad4 EAS

AF:

0.000266

Gnomad4 SAS

AF:

0.000286

Gnomad4 FIN

AF:

0.00477

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.00346

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Haim-Munk syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

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

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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