NM_001814.6:c.173-8_173-7dupTT

Variant names:

• chr11-88335088-G-GAA
• rs11326739
• NM_001814.6:c.173-8_173-7dupTT

Variant summary

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

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
• 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6	c.173-8_173-7dupTT		splice_region_variant, intron_variant	Intron 1 of 6	ENST00000227266.10	NP_001805.4
CTSC	NM_001114173.3	c.173-8_173-7dupTT		splice_region_variant, intron_variant	Intron 1 of 3		NP_001107645.1
CTSC	NM_148170.5	c.173-8_173-7dupTT		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.173-8_173-7dupTT		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: 0.0000678

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

GnomAD2 exomes AF: 0.000859 AC: 114 AN: 132778 AF XY: 0.000812

Gnomad AFR exome AF: 0.000419

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000805

Gnomad EAS exome AF: 0.000964

Gnomad FIN exome AF: 0.000452

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.000989 AC: 1099 AN: 1111728 Hom.: 0 Cov.: 16 AF XY: 0.000929 AC XY: 521 AN XY: 560854

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

African (AFR) AF: 0.000855 AC: 22 AN: 25728

American (AMR) AF: 0.000641 AC: 23 AN: 35868

Ashkenazi Jewish (ASJ) AF: 0.000506 AC: 11 AN: 21720

East Asian (EAS) AF: 0.000314 AC: 11 AN: 35016

South Asian (SAS) AF: 0.000417 AC: 30 AN: 71904

European-Finnish (FIN) AF: 0.000234 AC: 10 AN: 42794

Middle Eastern (MID) AF: 0.000482 AC: 2 AN: 4152

European-Non Finnish (NFE) AF: 0.00117 AC: 967 AN: 827346

Other (OTH) AF: 0.000487 AC: 23 AN: 47200

⚠️ 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: 108142 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 52116

African (AFR) AF: 0.0000677 AC: 2 AN: 29548

American (AMR) AF: 0.00 AC: 0 AN: 10864

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3764

South Asian (SAS) AF: 0.00 AC: 0 AN: 3496

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 182

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49276

Other (OTH) AF: 0.00 AC: 0 AN: 1446

Alfa AF: 0.00123 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11326739; hg19: chr11-88068256;