chr11-88294052-GCA-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_001814.6(CTSC):c.1344_1345del(p.Ala449AsnfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.000018 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. C448C) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
CTSC
NM_001814.6 frameshift
NM_001814.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.98
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0345 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
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.1344_1345del | p.Ala449AsnfsTer2 | frameshift_variant | 7/7 | ENST00000227266.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTSC | ENST00000227266.10 | c.1344_1345del | p.Ala449AsnfsTer2 | frameshift_variant | 7/7 | 1 | NM_001814.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151952Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251052Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135648
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461832Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 727212
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151952Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74202
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 21, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2016 | The c.1344_1345delTG variant in the CTSC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1344_1345delTG variant causes a frameshift starting with codon Alanine 449, changes this amino acid to a Asparagine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Ala449AsnfsX2. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1344_1345delTG variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. We interpret c.1344_1345delTG as a variant of uncertain significance. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at