17-8237472-C-T

Position:

chr17-8237472-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025099.6(CTC1):c.695G>A(p.Arg232Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,824 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 6 hom., cov: 29)

Exomes 𝑓: 0.0018 ( 39 hom. )

Consequence

CTC1
NM_025099.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.859

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046502054).

BP6

Variant 17-8237472-C-T is Benign according to our data. Variant chr17-8237472-C-T is described in ClinVar as [Benign]. Clinvar id is 210797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8237472-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00107 (163/151958) while in subpopulation SAS AF= 0.0302 (145/4806). AF 95% confidence interval is 0.0262. There are 6 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTC1	NM_025099.6 linkuse as main transcript	c.695G>A	p.Arg232Gln	missense_variant	5/23	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.695G>A	p.Arg232Gln	missense_variant	5/23		NM_025099.6	ENSP00000498499.1		Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

162

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.0299

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00382

AC:

954

AN:

249578

Hom.:

AF XY:

0.00495

AC XY:

670

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00122

Gnomad SAS exome

AF:

0.0294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00330

GnomAD4 exome

AF:

0.00184

AC:

2692

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

1878

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000705

Gnomad4 SAS exome

AF:

0.0285

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.00245

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

151958

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000968

Gnomad4 SAS

AF:

0.0302

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000603

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00424

AC:

513

Asia WGS

AF:

0.0340

AC:

117

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dyskeratosis congenita

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 18, 2017

- -

Cerebroretinal microangiopathy with calcifications and cysts 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

CTC1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2019

This variant is classified as 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

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

REVEL

Benign

0.064

Sift

Benign

0.15

Sift4G

Benign

0.22

Polyphen

0.086

Vest4

0.22

MVP

0.59

MPC

0.14

ClinPred

0.015

GERP RS

0.99

Varity_R

0.054

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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