11-88335088-GAAAA-GA

Variant names:

• chr11-88335088-GAAA-G
• rs11326739
• NM_001814.6:c.173-9_173-7delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001814.6(CTSC):​c.173-9_173-7delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000554 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, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Papillon-Lefevre disease

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Haim-Munk syndrome

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• ectodermal dysplasia syndrome

  Inheritance: AR Classification: STRONG Submitted by: Illumina
• periodontitis, aggressive 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6	c.173-9_173-7delTTT		splice_region_variant, intron_variant	Intron 1 of 6	ENST00000227266.10	NP_001805.4
CTSC	NM_001114173.3	c.173-9_173-7delTTT		splice_region_variant, intron_variant	Intron 1 of 3		NP_001107645.1
CTSC	NM_148170.5	c.173-9_173-7delTTT		splice_region_variant, intron_variant	Intron 1 of 3		NP_680475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10	c.173-9_173-7delTTT		splice_region_variant, intron_variant	Intron 1 of 6	1	NM_001814.6	ENSP00000227266.4

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

GnomAD2 exomes AF: 0.0000828 AC: 11 AN: 132778 AF XY: 0.0000688

Gnomad AFR exome AF: 0.000105

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000964

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000842

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000116 AC: 3 AN: 25866

American (AMR) AF: 0.0000555 AC: 2 AN: 36066

Ashkenazi Jewish (ASJ) AF: 0.0000458 AC: 1 AN: 21832

East Asian (EAS) AF: 0.0000284 AC: 1 AN: 35230

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4164

European-Non Finnish (NFE) AF: 0.0000660 AC: 55 AN: 833478

Other (OTH) AF: 0.0000631 AC: 3 AN: 47526

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00 AC: 0 AN: 29484

American (AMR) AF: 0.000184 AC: 2 AN: 10854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2486

East Asian (EAS) AF: 0.00 AC: 0 AN: 3774

South Asian (SAS) AF: 0.00 AC: 0 AN: 3510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49282

Other (OTH) AF: 0.00 AC: 0 AN: 1440

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11326739; hg19: chr11-88068256; COSMIC: COSV57057585;