rs3027238

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025099.6(CTC1):c.2458A>G(p.Ile820Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,614,034 control chromosomes in the GnomAD database, including 747,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I820T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.95 ( 68212 hom., cov: 31)

Exomes 𝑓: 0.96 ( 679060 hom. )

Consequence

CTC1
NM_025099.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.260

Publications

38 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

CTC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.026743E-7).

BP6

Variant 17-8231743-T-C is Benign according to our data. Variant chr17-8231743-T-C is described in ClinVar as Benign. ClinVar VariationId is 128860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6 link	c.2458A>G	p.Ile820Val	missense_variant	Exon 14 of 23	ENST00000651323.1	NP_079375.3	Q2NKJ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1 link	c.2458A>G	p.Ile820Val	missense_variant	Exon 14 of 23		NM_025099.6	ENSP00000498499.1		Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.946

AC:

143894

AN:

152144

Hom.:

68160

Cov.:

show subpopulations

Gnomad AFR

AF:

0.923

Gnomad AMI

AF:

0.911

Gnomad AMR

AF:

0.886

Gnomad ASJ

AF:

0.849

Gnomad EAS

AF:

0.989

Gnomad SAS

AF:

0.940

Gnomad FIN

AF:

0.993

Gnomad MID

AF:

0.924

Gnomad NFE

AF:

0.969

Gnomad OTH

AF:

0.937

GnomAD2 exomes

AF:

0.947

AC:

236367

AN:

249528

AF XY:

0.950

show subpopulations

Gnomad AFR exome

AF:

0.923

Gnomad AMR exome

AF:

0.870

Gnomad ASJ exome

AF:

0.859

Gnomad EAS exome

AF:

0.992

Gnomad FIN exome

AF:

0.991

Gnomad NFE exome

AF:

0.970

Gnomad OTH exome

AF:

0.948

GnomAD4 exome

AF:

0.963

AC:

1408345

AN:

1461772

Hom.:

679060

Cov.:

AF XY:

0.963

AC XY:

700130

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.919

AC:

30768

AN:

33476

American (AMR)

AF:

0.871

AC:

38963

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.862

AC:

22538

AN:

26134

East Asian (EAS)

AF:

0.990

AC:

39312

AN:

39700

South Asian (SAS)

AF:

0.934

AC:

80580

AN:

86250

European-Finnish (FIN)

AF:

0.990

AC:

52897

AN:

53420

Middle Eastern (MID)

AF:

0.901

AC:

5195

AN:

5768

European-Non Finnish (NFE)

AF:

0.972

AC:

1080607

AN:

1111914

Other (OTH)

AF:

0.952

AC:

57485

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2816

5632

8447

11263

14079

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21638

43276

64914

86552

108190

<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:

0.946

AC:

144004

AN:

152262

Hom.:

68212

Cov.:

AF XY:

0.945

AC XY:

70324

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.923

AC:

38321

AN:

41526

American (AMR)

AF:

0.886

AC:

13548

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.849

AC:

2948

AN:

3472

East Asian (EAS)

AF:

0.989

AC:

5124

AN:

5182

South Asian (SAS)

AF:

0.941

AC:

4541

AN:

4826

European-Finnish (FIN)

AF:

0.993

AC:

10540

AN:

10614

Middle Eastern (MID)

AF:

0.925

AC:

272

AN:

294

European-Non Finnish (NFE)

AF:

0.969

AC:

65906

AN:

68026

Other (OTH)

AF:

0.934

AC:

1975

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

397

795

1192

1590

1987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.956

Hom.:

210792

Bravo

AF:

0.939

TwinsUK

AF:

0.974

AC:

3610

ALSPAC

AF:

0.977

AC:

3765

ESP6500AA

AF:

0.929

AC:

3604

ESP6500EA

AF:

0.964

AC:

7996

ExAC

AF:

0.951

AC:

114876

Asia WGS

AF:

0.944

AC:

3283

AN:

3478

EpiCase

AF:

0.963

EpiControl

AF:

0.964

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebroretinal microangiopathy with calcifications and cysts 1

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.2

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.16

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.38

MetaRNN

Benign

6.0e-7

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

PhyloP100

0.26

PrimateAI

Benign

0.29

PROVEAN

Benign

0.18

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.020

MPC

0.098

ClinPred

0.00029

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

gMVP

0.095

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over