rs200609323
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_025099.6(CTC1):c.2758+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_025099.6 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTC1 | NM_025099.6 | c.2758+1G>T | splice_donor_variant | ENST00000651323.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTC1 | ENST00000651323.1 | c.2758+1G>T | splice_donor_variant | NM_025099.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249566Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135402
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461790Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727202
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74434
ClinVar
Submissions by phenotype
Dyskeratosis congenita Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change affects a donor splice site in intron 16 of the CTC1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CTC1 are known to be pathogenic (PMID: 22267198, 22387016). This variant is present in population databases (rs200609323, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with cerebral microangiopathy with calcifications and cysts (PMID: 25197929). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 529185). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 08, 2020 | - - |
Cerebroretinal microangiopathy with calcifications and cysts 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at