17-8229445-T-C

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.3013A>G(p.Ile1005Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,610,584 control chromosomes in the GnomAD database, including 509,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1005F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.77 ( 45623 hom., cov: 32)

Exomes 𝑓: 0.79 ( 463418 hom. )

Consequence

CTC1
NM_025099.6 missense, splice_region

Scores

Splicing: ADA: 0.00005087

Clinical Significance

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

Conservation

PhyloP100: -0.940

Publications

40 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=7.250869E-7).

BP6

Variant 17-8229445-T-C is Benign according to our data. Variant chr17-8229445-T-C is described in ClinVar as Benign. ClinVar VariationId is 128861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6 link	c.3013A>G	p.Ile1005Val	missense_variant, splice_region_variant	Exon 19 of 23	ENST00000651323.1	NP_079375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1 link	c.3013A>G	p.Ile1005Val	missense_variant, splice_region_variant	Exon 19 of 23		NM_025099.6	ENSP00000498499.1

Frequencies

GnomAD3 genomes

AF:

0.769

AC:

116828

AN:

151964

Hom.:

45581

Cov.:

show subpopulations

Gnomad AFR

AF:

0.765

Gnomad AMI

AF:

0.747

Gnomad AMR

AF:

0.657

Gnomad ASJ

AF:

0.651

Gnomad EAS

AF:

0.377

Gnomad SAS

AF:

0.774

Gnomad FIN

AF:

0.855

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.820

Gnomad OTH

AF:

0.744

GnomAD2 exomes

AF:

0.737

AC:

183172

AN:

248494

AF XY:

0.748

show subpopulations

Gnomad AFR exome

AF:

0.761

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.667

Gnomad EAS exome

AF:

0.382

Gnomad FIN exome

AF:

0.855

Gnomad NFE exome

AF:

0.819

Gnomad OTH exome

AF:

0.750

GnomAD4 exome

AF:

0.791

AC:

1154369

AN:

1458502

Hom.:

463418

Cov.:

AF XY:

0.792

AC XY:

575053

AN XY:

725762

show subpopulations

African (AFR)

AF:

0.756

AC:

25237

AN:

33382

American (AMR)

AF:

0.564

AC:

25208

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.668

AC:

17437

AN:

26098

East Asian (EAS)

AF:

0.347

AC:

13780

AN:

39680

South Asian (SAS)

AF:

0.781

AC:

67259

AN:

86174

European-Finnish (FIN)

AF:

0.857

AC:

45707

AN:

53342

Middle Eastern (MID)

AF:

0.681

AC:

3892

AN:

5716

European-Non Finnish (NFE)

AF:

0.820

AC:

909871

AN:

1109188

Other (OTH)

AF:

0.763

AC:

45978

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

10554

21108

31662

42216

52770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20686

41372

62058

82744

103430

<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:

0.769

AC:

116921

AN:

152082

Hom.:

45623

Cov.:

AF XY:

0.766

AC XY:

56981

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.765

AC:

31735

AN:

41474

American (AMR)

AF:

0.657

AC:

10025

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.651

AC:

2258

AN:

3470

East Asian (EAS)

AF:

0.376

AC:

1938

AN:

5152

South Asian (SAS)

AF:

0.776

AC:

3741

AN:

4820

European-Finnish (FIN)

AF:

0.855

AC:

9054

AN:

10592

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.820

AC:

55731

AN:

67988

Other (OTH)

AF:

0.741

AC:

1567

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1356

2712

4068

5424

6780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.788

Hom.:

160841

Bravo

AF:

0.750

TwinsUK

AF:

0.835

AC:

3098

ALSPAC

AF:

0.820

AC:

3160

ESP6500AA

AF:

0.773

AC:

3039

ESP6500EA

AF:

0.814

AC:

6762

ExAC

AF:

0.750

AC:

90589

Asia WGS

AF:

0.619

AC:

2156

AN:

3478

EpiCase

AF:

0.793

EpiControl

AF:

0.796

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

- -

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 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 81. Only high quality variants are reported. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cerebroretinal microangiopathy with calcifications and cysts 1

Benign:2

Nov 22, 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 13, 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

0.065

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.015

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.086

T;T

MetaRNN

Benign

7.3e-7

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.7

N;.

PhyloP100

-0.94

PrimateAI

Benign

0.27

PROVEAN

Benign

0.36

N;.

REVEL

Benign

0.14

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.0090

MPC

0.097

ClinPred

0.0032

GERP RS

-3.3

PromoterAI

0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.072

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000051

dbscSNV1_RF

Benign

0.0040

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

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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