17-8234592-G-T

Position:

• chr17-8234592-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025099.6(CTC1):​c.1681C>A​(p.Arg561Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0920

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054629296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTC1	NM_025099.6	c.1681C>A	p.Arg561Ser	missense_variant	10/23	ENST00000651323.1	NP_079375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1	c.1681C>A	p.Arg561Ser	missense_variant	10/23		NM_025099.6	ENSP00000498499	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000166 AC: 4 AN: 241520 Hom.: 0 AF XY: 0.0000229 AC XY: 3 AN XY: 131130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458372 Hom.: 0 Cov.: 34 AF XY: 0.00000552 AC XY: 4 AN XY: 725138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.1681C>A (p.R561S) alteration is located in exon 10 (coding exon 10) of the CTC1 gene. This alteration results from a C to A substitution at nucleotide position 1681, causing the arginine (R) at amino acid position 561 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 529174). This variant has not been reported in the literature in individuals affected with CTC1-related conditions. This variant is present in population databases (rs202212634, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 561 of the CTC1 protein (p.Arg561Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.65
DANN	Benign	0.63
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.40	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.0040	B
Vest4		0.11
MVP		0.37
MPC		0.13
ClinPred		0.021	T
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs202212634; hg19: chr17-8137910;