rs199473673
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4
The NM_025099.6(CTC1):c.680C>T(p.Ala227Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000043 ( 0 hom. )
Consequence
CTC1
NM_025099.6 missense
NM_025099.6 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 4.49
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-8237487-G-A is Pathogenic according to our data. Variant chr17-8237487-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31004.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-8237487-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.26150215). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTC1 | NM_025099.6 | c.680C>T | p.Ala227Val | missense_variant | 5/23 | ENST00000651323.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTC1 | ENST00000651323.1 | c.680C>T | p.Ala227Val | missense_variant | 5/23 | NM_025099.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 151820Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.000152 AC: 38AN: 249558Hom.: 0 AF XY: 0.000148 AC XY: 20AN XY: 135392
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GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727242
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GnomAD4 genome ? AF: 0.000112 AC: 17AN: 151936Hom.: 0 Cov.: 29 AF XY: 0.000175 AC XY: 13AN XY: 74260
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cerebroretinal microangiopathy with calcifications and cysts 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 09, 2012 | - - |
Dyskeratosis congenita Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CTC1 function (PMID: 24115768, 29481669). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 31004). This missense change has been observed in individual(s) with cerebroretinal microangiopathy with calcifications and cysts (PMID: 22387016). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199473673, gnomAD 0.2%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 227 of the CTC1 protein (p.Ala227Val). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
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Splicing
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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