rs3027238

Positions:

• chr17-8231743-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025099.6(CTC1):​c.2458A>G​(p.Ile820Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,614,034 control chromosomes in the GnomAD database, including 747,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I820T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.95 (68212 hom., cov: 31)
  • Exomes 𝑓: 0.96 (679060 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.260

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.026743E-7).
• BP6: Variant 17-8231743-T-C is Benign according to our data. Variant chr17-8231743-T-C is described in ClinVar as [Benign]. Clinvar id is 128860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8231743-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTC1	NM_025099.6	c.2458A>G	p.Ile820Val	missense_variant	14/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1	c.2458A>G	p.Ile820Val	missense_variant	14/23		NM_025099.6	P1

Frequencies

GnomAD3 genomes AF: 0.946 AC: 143894 AN: 152144 Hom.: 68160 Cov.: 31

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.886

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.940

Gnomad FIN AF: 0.993

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.969

Gnomad OTH AF: 0.937

GnomAD3 exomes AF: 0.947 AC: 236367 AN: 249528 Hom.: 112221 AF XY: 0.950 AC XY: 128618 AN XY: 135392

Gnomad AFR exome AF: 0.923

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.859

Gnomad EAS exome AF: 0.992

Gnomad SAS exome AF: 0.934

Gnomad FIN exome AF: 0.991

Gnomad NFE exome AF: 0.970

Gnomad OTH exome AF: 0.948

GnomAD4 exome AF: 0.963 AC: 1408345 AN: 1461772 Hom.: 679060 Cov.: 50 AF XY: 0.963 AC XY: 700130 AN XY: 727186

Gnomad4 AFR exome AF: 0.919

Gnomad4 AMR exome AF: 0.871

Gnomad4 ASJ exome AF: 0.862

Gnomad4 EAS exome AF: 0.990

Gnomad4 SAS exome AF: 0.934

Gnomad4 FIN exome AF: 0.990

Gnomad4 NFE exome AF: 0.972

Gnomad4 OTH exome AF: 0.952

GnomAD4 genome AF: 0.946 AC: 144004 AN: 152262 Hom.: 68212 Cov.: 31 AF XY: 0.945 AC XY: 70324 AN XY: 74428

Gnomad4 AFR AF: 0.923

Gnomad4 AMR AF: 0.886

Gnomad4 ASJ AF: 0.849

Gnomad4 EAS AF: 0.989

Gnomad4 SAS AF: 0.941

Gnomad4 FIN AF: 0.993

Gnomad4 NFE AF: 0.969

Gnomad4 OTH AF: 0.934

Alfa AF: 0.959 Hom.: 153419

Bravo AF: 0.939

TwinsUK AF: 0.974 AC: 3610

ALSPAC AF: 0.977 AC: 3765

ESP6500AA AF: 0.929 AC: 3604

ESP6500EA AF: 0.964 AC: 7996

ExAC AF: 0.951 AC: 114876

Asia WGS AF: 0.944 AC: 3283 AN: 3478

EpiCase AF: 0.963

EpiControl AF: 0.964

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
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	- -

Dyskeratosis congenita Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 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 provided Benign:1 Other: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. -

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	0.067
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.2
DANN	Benign	0.20
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.098
ClinPred		0.00029	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs3027238; hg19: chr17-8135061;