rs376349076

chr17-8229194-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025099.6(CTC1):c.3169C>T(p.Arg1057Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1057H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.56

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTC1	NM_025099.6	c.3169C>T	p.Arg1057Cys	missense_variant	20/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1	c.3169C>T	p.Arg1057Cys	missense_variant	20/23		NM_025099.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249550 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000487 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 13, 2020

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.3169C>T (p.R1057C) alteration is located in exon 20 (coding exon 20) of the CTC1 gene. This alteration results from a C to T substitution at nucleotide position 3169, causing the arginine (R) at amino acid position 1057 to be replaced by a cysteine (C). 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

Invitae

Mar 07, 2023

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 403760). This variant has not been reported in the literature in individuals affected with CTC1-related conditions. This variant is present in population databases (rs376349076, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1057 of the CTC1 protein (p.Arg1057Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.71
MPC		0.62
ClinPred		0.71	D
GERP RS		4.4
Varity_R		0.20
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs376349076; hg19: chr17-8132512;