chr17-8232128-G-A

Position:

• chr17-8232128-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025099.6(CTC1):​c.2160C>T​(p.Thr720=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,528,728 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (221 hom., cov: 32)
  • Exomes 𝑓: 0.018 (444 hom.)
• Consequence: CTC1 NM_025099.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.764

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-8232128-G-A is Benign according to our data. Variant chr17-8232128-G-A is described in ClinVar as [Benign]. Clinvar id is 326074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.764 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTC1	NM_025099.6	c.2160C>T	p.Thr720=	synonymous_variant	13/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1	c.2160C>T	p.Thr720=	synonymous_variant	13/23		NM_025099.6	P1

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5901 AN: 152152 Hom.: 220 Cov.: 32

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0301 AC: 4983 AN: 165530 Hom.: 172 AF XY: 0.0266 AC XY: 2332 AN XY: 87834

Gnomad AFR exome AF: 0.0755

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.0393

Gnomad EAS exome AF: 0.00831

Gnomad SAS exome AF: 0.0127

Gnomad FIN exome AF: 0.00563

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0177 AC: 24301 AN: 1376458 Hom.: 444 Cov.: 32 AF XY: 0.0171 AC XY: 11615 AN XY: 677292

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.0373

Gnomad4 EAS exome AF: 0.00979

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00635

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0224

GnomAD4 genome AF: 0.0388 AC: 5914 AN: 152270 Hom.: 221 Cov.: 32 AF XY: 0.0397 AC XY: 2958 AN XY: 74456

Gnomad4 AFR AF: 0.0747

Gnomad4 AMR AF: 0.0932

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0227 Hom.: 134

Bravo AF: 0.0456

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2016	- -

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	Invitae	Feb 01, 2024	- -

Cerebroretinal microangiopathy with calcifications and cysts 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.5
DANN	Benign	0.31

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

LitVar

Other links and lift over

dbSNP: rs3027235; hg19: chr17-8135446;