17-8234591-C-G

Variant names:

• chr17-8234591-C-G
• rs373690929
• NM_025099.6:c.1682G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025099.6(CTC1):​c.1682G>C​(p.Arg561Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. R561H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.260
• Publications: 0 publications found

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]

CTC1 Gene-Disease associations (from GenCC):

• cerebroretinal microangiopathy with calcifications and cysts 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• dyskeratosis congenita

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Coats plus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14598086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6	c.1682G>C	p.Arg561Pro	missense_variant	Exon 10 of 23	ENST00000651323.1	NP_079375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1	c.1682G>C	p.Arg561Pro	missense_variant	Exon 10 of 23		NM_025099.6	ENSP00000498499.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240598 AF XY: 0.00000765

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000916

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457924 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 724920

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 43950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110286

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita Uncertain:1

Jan 09, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CTC1-related disease. This sequence change replaces arginine with proline at codon 561 of the CTC1 protein (p.Arg561Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.7
DANN	Benign	0.63
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.26
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.61	P
Vest4		0.32
MutPred		0.24		Loss of helix (P = 0.0167);
MVP		0.46
MPC		0.29
ClinPred		0.093	T
GERP RS		-2.3
Varity_R		0.51
gMVP		0.65
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs373690929; hg19: chr17-8137909;