rs73244859

Positions:

• chr17-8238461-T-C
• chr17-8238461-T-G

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.366A>G​(p.Ala122=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,614,188 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (104 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (86 hom.)
• Consequence: CTC1 NM_025099.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.326

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=-0.9).
• BP6: Variant 17-8238461-T-C is Benign according to our data. Variant chr17-8238461-T-C is described in ClinVar as [Benign]. Clinvar id is 326087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.326 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTC1	NM_025099.6	c.366A>G	p.Ala122=	synonymous_variant	3/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1	c.366A>G	p.Ala122=	synonymous_variant	3/23		NM_025099.6	P1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2979 AN: 152184 Hom.: 104 Cov.: 31

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00521 AC: 1300 AN: 249574 Hom.: 25 AF XY: 0.00397 AC XY: 538 AN XY: 135402

Gnomad AFR exome AF: 0.0695

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000612

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00213 AC: 3120 AN: 1461886 Hom.: 86 Cov.: 31 AF XY: 0.00185 AC XY: 1342 AN XY: 727248

Gnomad4 AFR exome AF: 0.0712

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.00239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.00447

GnomAD4 genome AF: 0.0196 AC: 2981 AN: 152302 Hom.: 104 Cov.: 31 AF XY: 0.0192 AC XY: 1429 AN XY: 74474

Gnomad4 AFR AF: 0.0679

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00636 Hom.: 16

Bravo AF: 0.0216

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 05, 2016

- -

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 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs73244859; hg19: chr17-8141779;