chr17-8232427-A-C

Position:

chr17-8232427-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_025099.6(CTC1):c.1994T>G(p.Val665Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000942 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

CTC1
NM_025099.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.47

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 Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-8232427-A-C is Pathogenic according to our data. Variant chr17-8232427-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 31002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8232427-A-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.38792092). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTC1	NM_025099.6 linkuse as main transcript	c.1994T>G	p.Val665Gly	missense_variant	12/23	ENST00000651323.1	NP_079375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1 linkuse as main transcript	c.1994T>G	p.Val665Gly	missense_variant	12/23		NM_025099.6	ENSP00000498499	P1	Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000200

AC:

AN:

249480

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135354

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00223

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727226

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00213

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000237

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00340

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebroretinal microangiopathy with calcifications and cysts 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2024	Variant summary: CTC1 c.1994T>G (p.Val665Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 249480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CTC1 causing cerebroretinal microangiopathy with calcifications and cysts 1 (0.0002 vs 0.0011), allowing no conclusion about variant significance. c.1994T>G has been reported in the literature in multiple individuals affected with cerebroretinal microangiopathy with calcifications (CRMCC), including cases where it has been confirmed to be in trans with a pathogenic variant and in families where it has segregated with the disease phenotype (e.g. Polvi_2012, Mansukhani_2017, Feurstein_2021). These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence suggesting that the variant has an impact on protein function, reducing telomere association and impairing response to replication stress (e.g. Chen_2013, Wang_2018). The following publications have been ascertained in the context of this evaluation (PMID: 24115768, 28864049, 22387016, 29481669, 33510405). ClinVar contains an entry for this variant (Variation ID: 31002). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2012	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2023

Published functional studies demonstrate a damaging effect with impaired telomere replication, global genome instabilities, and decreased cell proliferation and survival (Gu et al., 2013; Chen et al., 2013, Wang et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23869908, 24115768, 22387016, 29481669, 33510405, 33780718) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.70

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.56

M_CAP

Benign

0.063

MetaRNN

Benign

0.39

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.012

Polyphen

0.99

Vest4

0.83

MutPred

0.65

Loss of stability (P = 0.0081);

MVP

0.75

MPC

0.59

ClinPred

0.30

GERP RS

5.2

Varity_R

0.55

gMVP

0.51

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

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