11-88335088-GAAA-GAAAAA

Position:

• chr11-88335088-GAAA-GAAAAA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_001814.6(CTSC):​c.173-8_173-7dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,219,870 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00099 (0 hom.)
• Consequence: CTSC NM_001814.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000989 (1099/1111728) while in subpopulation NFE AF= 0.00117 (967/827346). AF 95% confidence interval is 0.00111. There are 0 homozygotes in gnomad4_exome. There are 521 alleles in male gnomad4_exome subpopulation. Median coverage is 16. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSC	NM_001814.6	c.173-8_173-7dupTT		splice_region_variant, intron_variant		ENST00000227266.10	NP_001805.4
CTSC	NM_001114173.3	c.173-8_173-7dupTT		splice_region_variant, intron_variant			NP_001107645.1
CTSC	NM_148170.5	c.173-8_173-7dupTT		splice_region_variant, intron_variant			NP_680475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10	c.173-8_173-7dupTT		splice_region_variant, intron_variant		1	NM_001814.6	ENSP00000227266.4

Frequencies

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

Gnomad AFR AF: 0.0000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000989 AC: 1099 AN: 1111728 Hom.: 0 Cov.: 16 AF XY: 0.000929 AC XY: 521 AN XY: 560854

Gnomad4 AFR exome AF: 0.000855

Gnomad4 AMR exome AF: 0.000641

Gnomad4 ASJ exome AF: 0.000506

Gnomad4 EAS exome AF: 0.000314

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.000234

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.000487

GnomAD4 genome AF: 0.0000185 AC: 2 AN: 108142 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 52116

Gnomad4 AFR AF: 0.0000677

Gnomad4 AMR AF: 0.00

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

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;