NM_001814.6:c.173-10_173-7dupTTTT

Variant summary

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

The NM_001814.6(CTSC):​c.173-10_173-7dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 1,120,630 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: not found (cov: 29)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CTSC
NM_001814.6 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.410

Publications

0 publications found
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
CTSCNM_001814.6 linkc.173-10_173-7dupTTTT splice_region_variant, intron_variant Intron 1 of 6 ENST00000227266.10 NP_001805.4 P53634-1
CTSCNM_001114173.3 linkc.173-10_173-7dupTTTT splice_region_variant, intron_variant Intron 1 of 3 NP_001107645.1 P53634-3
CTSCNM_148170.5 linkc.173-10_173-7dupTTTT splice_region_variant, intron_variant Intron 1 of 3 NP_680475.1 P53634-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTSCENST00000227266.10 linkc.173-10_173-7dupTTTT splice_region_variant, intron_variant Intron 1 of 6 1 NM_001814.6 ENSP00000227266.4 P53634-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
AF:
0.00000268
AC:
3
AN:
1120630
Hom.:
0
Cov.:
16
AF XY:
0.00
AC XY:
0
AN XY:
565320
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
25898
American (AMR)
AF:
0.00
AC:
0
AN:
36072
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21862
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35244
South Asian (SAS)
AF:
0.00
AC:
0
AN:
72328
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
42964
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4168
European-Non Finnish (NFE)
AF:
0.00000359
AC:
3
AN:
834504
Other (OTH)
AF:
0.00
AC:
0
AN:
47590
⚠️ 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.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.41

Splicing

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

Publications

Other links and lift over

dbSNP: rs11326739; hg19: chr11-88068256; API