rs201763299

chr11-88335088-G-Achr11-88335088-G-Cchr11-88335088-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 2/2 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

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]

ACMG classification

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	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSC	NM_001814.6	c.173-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000227266.10
CTSC	NM_001114173.3	c.173-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CTSC	NM_148170.5	c.173-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 864 AN: 107132 Hom.: 0 Cov.: 26 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.: 0 Cov.: 22 AF XY: 0.0311 AC XY: 17515 AN XY: 562334

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.: 0 Cov.: 26 AF XY: 0.00894 AC XY: 462 AN XY: 51654

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.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 08, 2020

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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

Other links and lift over

dbSNP: rs201763299; hg19: chr11-88068256; COSMIC: COSV57056754;