rs11326739

chr11-88335088-GAAA-Gchr11-88335088-GAAA-GAchr11-88335088-GAAA-GAAchr11-88335088-GAAA-GAAAAchr11-88335088-GAAA-GAAAAA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001814.6(CTSC):c.173-9_173-7del 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 0.0000554 in 1,227,488 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000059 (1 hom.)
• Consequence: CTSC NM_001814.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSC	NM_001814.6	c.173-9_173-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000227266.10
CTSC	NM_001114173.3	c.173-9_173-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CTSC	NM_148170.5	c.173-9_173-7del		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.173-9_173-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001814.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000185 AC: 2 AN: 108102 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000590 AC: 66 AN: 1119386 Hom.: 1 AF XY: 0.0000549 AC XY: 31 AN XY: 564786

Gnomad4 AFR exome AF: 0.000116

Gnomad4 AMR exome AF: 0.0000555

Gnomad4 ASJ exome AF: 0.0000458

Gnomad4 EAS exome AF: 0.0000284

Gnomad4 SAS exome AF: 0.0000138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000660

Gnomad4 OTH exome AF: 0.0000631

GnomAD4 genome AF: 0.0000185 AC: 2 AN: 108102 Hom.: 0 Cov.: 29 AF XY: 0.0000384 AC XY: 2 AN XY: 52066

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs11326739; hg19: chr11-88068256;