17-8232096-C-T

Variant names:

Variant summary

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

The NM_025099.6(CTC1):c.2192G>A(p.Arg731Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,548,548 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R731W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

CTC1
NM_025099.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 2.54

Publications

3 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.063993394).

BP6

Variant 17-8232096-C-T is Benign according to our data. Variant chr17-8232096-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210794.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6 link	c.2192G>A	p.Arg731Gln	missense_variant	Exon 13 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.2192G>A	p.Arg731Gln	missense_variant	Exon 13 of 23		NM_025099.6	ENSP00000498499.1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000430

AC:

AN:

181508

AF XY:

0.000352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000856

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00172

Gnomad NFE exome

AF:

0.000501

Gnomad OTH exome

AF:

0.000719

GnomAD4 exome

AF:

0.000633

AC:

884

AN:

1396446

Hom.:

Cov.:

AF XY:

0.000615

AC XY:

424

AN XY:

689922

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30964

American (AMR)

AF:

0.0000913

AC:

AN:

32866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21032

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39350

South Asian (SAS)

AF:

0.00

AC:

AN:

73642

European-Finnish (FIN)

AF:

0.00176

AC:

AN:

50570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5404

European-Non Finnish (NFE)

AF:

0.000699

AC:

759

AN:

1085094

Other (OTH)

AF:

0.000539

AC:

AN:

57524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

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:

0.000473

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41418

American (AMR)

AF:

0.000327

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000573

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000444

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000728

AC:

ExAC

AF:

0.000374

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

- -

Sep 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

May 07, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Sep 28, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Uncertain:1Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Uncertain:1

May 04, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 25, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CTC1-related disorder

Benign:1

May 25, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.071

MetaRNN

Benign

0.064

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.6

PhyloP100

2.5

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.49

Sift

Benign

0.11

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.41

MVP

0.83

MPC

0.61

ClinPred

0.12

GERP RS

5.6

Varity_R

0.39

gMVP

0.43

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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