rs202138550

Positions:

chr17-8229943-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_025099.6(CTC1):c.2959C>T(p.Arg987Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,614,082 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CTC1
NM_025099.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.11

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 links:

CTC1 (HGNC:):

CTC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-8229943-G-A is Pathogenic according to our data. Variant chr17-8229943-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8229943-G-A is described in Lovd as [Pathogenic]. Variant chr17-8229943-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTC1	NM_025099.6 linkuse as main transcript	c.2959C>T	p.Arg987Trp	missense_variant	18/23	ENST00000651323.1	NP_079375.3	Q2NKJ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1 linkuse as main transcript	c.2959C>T	p.Arg987Trp	missense_variant	18/23		NM_025099.6	ENSP00000498499.1		Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000561

AC:

AN:

249528

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000827

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebroretinal microangiopathy with calcifications and cysts 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 22, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Dyskeratosis congenita

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 987 of the CTC1 protein (p.Arg987Trp). This variant is present in population databases (rs202138550, gnomAD 0.009%). This missense change has been observed in individuals with Coats plus syndrome (PMID: 22267198, 22899577). ClinVar contains an entry for this variant (Variation ID: 30996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTC1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTC1 function (PMID: 23869908, 24115768). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.31

T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.8

D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.024

D;.

Sift4G

Uncertain

0.022

D;D

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.51

Loss of methylation at R987 (P = 0.0651);.;

MVP

0.75

MPC

0.52

ClinPred

0.71

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: 25

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over