rs3826543

Positions:

chr17-8229445-T-C

Variant summary

Our verdict is Benign. Variant got -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. 17/22 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 (★★).

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

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:

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=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 id is 128861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8229445-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
CTC1	NM_025099.6 link	c.3013A>G	p.Ile1005Val	missense_variant, splice_region_variant	19/23	ENST00000651323.1	NP_079375.3	Q2NKJ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1 link	c.3013A>G	p.Ile1005Val	missense_variant, splice_region_variant	19/23		NM_025099.6	ENSP00000498499.1		Q2NKJ3-1

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

GnomAD3 exomes

AF:

0.737

AC:

183172

AN:

248494

Hom.:

69919

AF XY:

0.748

AC XY:

100920

AN XY:

134888

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 SAS exome

AF:

0.780

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

Gnomad4 AFR exome

AF:

0.756

Gnomad4 AMR exome

AF:

0.564

Gnomad4 ASJ exome

AF:

0.668

Gnomad4 EAS exome

AF:

0.347

Gnomad4 SAS exome

AF:

0.781

Gnomad4 FIN exome

AF:

0.857

Gnomad4 NFE exome

AF:

0.820

Gnomad4 OTH exome

AF:

0.763

GnomAD4 genome

AF:

0.769

AC:

116921

AN:

152082

Hom.:

45623

Cov.:

AF XY:

0.766

AC XY:

56981

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.765

Gnomad4 AMR

AF:

0.657

Gnomad4 ASJ

AF:

0.651

Gnomad4 EAS

AF:

0.376

Gnomad4 SAS

AF:

0.776

Gnomad4 FIN

AF:

0.855

Gnomad4 NFE

AF:

0.820

Gnomad4 OTH

AF:

0.741

Alfa

AF:

0.789

Hom.:

112138

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:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dyskeratosis congenita

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cerebroretinal microangiopathy with calcifications and cysts 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

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;.

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.072

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

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