Variant 11-88335088-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001814.6(CTSC):c.173-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,115,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0081 ( 0 hom., cov: 26)

Exomes 𝑓: 0.026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CTSC
NM_001814.6 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004712

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.26

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 11-88335088-G-A is Benign according to our data. Variant chr11-88335088-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 466226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-88335088-G-A is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
CTSC	NM_001814.6 linkuse as main transcript	c.173-6C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000227266.10	NP_001805.4
CTSC	NM_001114173.3 linkuse as main transcript	c.173-6C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001107645.1
CTSC	NM_148170.5 linkuse as main transcript	c.173-6C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_680475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.173-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001814.6	ENSP00000227266	P1	P53634-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

864

AN:

107132

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00527

Gnomad AMI

AF:

0.0125

Gnomad AMR

AF:

0.00584

Gnomad ASJ

AF:

0.00203

Gnomad EAS

AF:

0.00535

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.0382

Gnomad MID

AF:

0.00526

Gnomad NFE

AF:

0.00719

Gnomad OTH

AF:

0.00563

GnomAD4 exome

AF:

0.0265

AC:

29518

AN:

1115146

Hom.:

Cov.:

AF XY:

0.0311

AC XY:

17515

AN XY:

562334

show subpopulations

Gnomad4 AFR exome

AF:

0.0274

Gnomad4 AMR exome

AF:

0.0913

Gnomad4 ASJ exome

AF:

0.0570

Gnomad4 EAS exome

AF:

0.0347

Gnomad4 SAS exome

AF:

0.0696

Gnomad4 FIN exome

AF:

0.0962

Gnomad4 NFE exome

AF:

0.0153

Gnomad4 OTH exome

AF:

0.0206

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00812

AC:

870

AN:

107170

Hom.:

Cov.:

AF XY:

0.00894

AC XY:

462

AN XY:

51654

show subpopulations

Gnomad4 AFR

AF:

0.00533

Gnomad4 AMR

AF:

0.00583

Gnomad4 ASJ

AF:

0.00203

Gnomad4 EAS

AF:

0.00563

Gnomad4 SAS

AF:

0.00288

Gnomad4 FIN

AF:

0.0382

Gnomad4 NFE

AF:

0.00720

Gnomad4 OTH

AF:

0.00630

Alfa

AF:

0.0140

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.2

DANN

Benign

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000047

dbscSNV1_RF

Benign

0.0

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