rs376302717

chr17-8234513-T-C

Variant summary

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

The NM_025099.6(CTC1):c.1760A>G(p.Asn587Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,557,058 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. N587H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.32

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.1760A>G	p.Asn587Ser	missense_variant	10/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1	c.1760A>G	p.Asn587Ser	missense_variant	10/23		NM_025099.6	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000926 AC: 15 AN: 161998 Hom.: 0 AF XY: 0.0000816 AC XY: 7 AN XY: 85828

Gnomad AFR exome AF: 0.000115

Gnomad AMR exome AF: 0.0000799

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000929

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000612 AC: 86 AN: 1404842 Hom.: 0 Cov.: 34 AF XY: 0.0000620 AC XY: 43 AN XY: 693478

Gnomad4 AFR exome AF: 0.000125

Gnomad4 AMR exome AF: 0.000111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000601

Gnomad4 OTH exome AF: 0.0000686

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74432

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.000252 AC: 1

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000865 AC: 10

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

Jun 16, 2023

The c.1760A>G (p.N587S) alteration is located in exon 10 (coding exon 10) of the CTC1 gene. This alteration results from a A to G substitution at nucleotide position 1760, causing the asparagine (N) at amino acid position 587 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

Invitae

Nov 27, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 587 of the CTC1 protein (p.Asn587Ser). This variant is present in population databases (rs376302717, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CTC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 571638). 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 expected to disrupt CTC1 protein function with a positive predictive value of 80%. 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	0.32
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.68	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.022	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.81
MPC		0.51
ClinPred		0.38	T
GERP RS		4.3
Varity_R		0.23
gMVP		0.80

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: rs376302717; hg19: chr17-8137831;