rs369904656

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_025099.6(CTC1):​c.1207-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,606,484 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00054 ( 1 hom. )

Consequence

CTC1
NM_025099.6 splice_region, intron

Scores

2
Splicing: ADA: 0.0001110
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: -0.192

Publications

1 publications found
Variant links:
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]
CTC1 Gene-Disease associations (from GenCC):
  • cerebroretinal microangiopathy with calcifications and cysts 1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
  • dyskeratosis congenita
    Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • Coats plus syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant 17-8235289-G-A is Benign according to our data. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589. Variant chr17-8235289-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 459589.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTC1NM_025099.6 linkc.1207-4C>T splice_region_variant, intron_variant Intron 7 of 22 ENST00000651323.1 NP_079375.3 Q2NKJ3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTC1ENST00000651323.1 linkc.1207-4C>T splice_region_variant, intron_variant Intron 7 of 22 NM_025099.6 ENSP00000498499.1 Q2NKJ3-1

Frequencies

GnomAD3 genomes
AF:
0.000309
AC:
47
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000588
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000382
AC:
94
AN:
245802
AF XY:
0.000366
show subpopulations
Gnomad AFR exome
AF:
0.0000661
Gnomad AMR exome
AF:
0.000379
Gnomad ASJ exome
AF:
0.000101
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000649
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.000541
AC:
786
AN:
1454182
Hom.:
1
Cov.:
31
AF XY:
0.000510
AC XY:
369
AN XY:
723474
show subpopulations
African (AFR)
AF:
0.0000902
AC:
3
AN:
33264
American (AMR)
AF:
0.000471
AC:
21
AN:
44608
Ashkenazi Jewish (ASJ)
AF:
0.0000384
AC:
1
AN:
26054
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39622
South Asian (SAS)
AF:
0.000267
AC:
23
AN:
86136
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52928
Middle Eastern (MID)
AF:
0.00104
AC:
6
AN:
5750
European-Non Finnish (NFE)
AF:
0.000642
AC:
710
AN:
1105672
Other (OTH)
AF:
0.000366
AC:
22
AN:
60148
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.512
Heterozygous variant carriers
0
45
90
135
180
225
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
28
56
84
112
140
<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
AF:
0.000309
AC:
47
AN:
152302
Hom.:
0
Cov.:
32
AF XY:
0.000309
AC XY:
23
AN XY:
74474
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
AN:
41562
American (AMR)
AF:
0.000196
AC:
3
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.000588
AC:
40
AN:
68012
Other (OTH)
AF:
0.000473
AC:
1
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000452
Hom.:
0
Bravo
AF:
0.000438
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000763
EpiControl
AF:
0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Dyskeratosis congenita Uncertain:1Benign:2
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 20, 2020
Sema4, Sema4
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cerebroretinal microangiopathy with calcifications and cysts 1 Uncertain:2
Jul 15, 2021
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 16, 2018
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Benign:1
Apr 16, 2021
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

CTC1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
CADD
Benign
4.9
DANN
Benign
0.71
PhyloP100
-0.19
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=97/3
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00011
dbscSNV1_RF
Benign
0.044
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs369904656; hg19: chr17-8138607; API