rs1196342305
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_025099.6(CTC1):βc.440delβ(p.Ile147LysfsTer45) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000131 in 1,603,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 31)
Exomes π: 0.000014 ( 0 hom. )
Consequence
CTC1
NM_025099.6 frameshift
NM_025099.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.40
Genes affected
CTC1 (HGNC:26169): (CST telomere replication complex component 1) This gene encodes a component of the CST complex. This complex plays an essential role in protecting telomeres from degradation. This protein also forms a heterodimer with the CST complex subunit STN1 to form the enzyme alpha accessory factor. This enzyme regulates DNA replication. Mutations in this gene are the cause of cerebroretinal microangiopathy with calcifications and cysts. Alternate splicing results in both coding and non-coding variants. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-8238237-TA-T is Pathogenic according to our data. Variant chr17-8238237-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 529178.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CTC1 | NM_025099.6 | c.440del | p.Ile147LysfsTer45 | frameshift_variant | 4/23 | ENST00000651323.1 | NP_079375.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CTC1 | ENST00000651323.1 | c.440del | p.Ile147LysfsTer45 | frameshift_variant | 4/23 | NM_025099.6 | ENSP00000498499 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.0000138 AC: 20AN: 1451360Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 11AN XY: 720556
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74372
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dyskeratosis congenita Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 10, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with CTC1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile147Lysfs*45) in the CTC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTC1 are known to be pathogenic (PMID: 22267198, 22387016). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at