17-8228797-G-T

Position:

chr17-8228797-G-T

Variant summary

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

The NM_025099.6(CTC1):c.3317C>A(p.Ser1106Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CTC1
NM_025099.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.962

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.3317C>A	p.Ser1106Tyr	missense_variant	21/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1 linkuse as main transcript	c.3317C>A	p.Ser1106Tyr	missense_variant	21/23		NM_025099.6	P1	Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000642

AC:

AN:

249408

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000145

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:

0.0000442

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000112

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:

0.0000243

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000246

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000827

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CTC1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2024

The CTC1 c.3317C>A variant is predicted to result in the amino acid substitution p.Ser1106Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Dyskeratosis congenita

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1106 of the CTC1 protein (p.Ser1106Tyr). This variant is present in population databases (rs367822614, gnomAD 0.03%). 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: 529188). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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

0.12

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.53

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.53

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.64

MVP

0.73

MPC

0.57

ClinPred

0.22

GERP RS

4.6

Varity_R

0.40

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over