rs62620189

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025099.6(CTC1):c.2162G>C(p.Gly721Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,529,924 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G721S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 17 hom., cov: 32)

Exomes 𝑓: 0.016 ( 237 hom. )

Consequence

CTC1
NM_025099.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.933

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

dyskeratosis congenita
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
cerebroretinal microangiopathy with calcifications and cysts 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Coats plus syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CTC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045121014).

BP6

Variant 17-8232126-C-G is Benign according to our data. Variant chr17-8232126-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025099.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTC1	NM_025099.6	MANE Select	c.2162G>C	p.Gly721Ala	missense	Exon 13 of 23	NP_079375.3
CTC1	NM_001411067.1		c.2162G>C	p.Gly721Ala	missense	Exon 13 of 21	NP_001397996.1	J3KSZ1
CTC1	NR_046431.2		n.2077G>C		non_coding_transcript_exon	Exon 13 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTC1	ENST00000651323.1	MANE Select	c.2162G>C	p.Gly721Ala	missense	Exon 13 of 23	ENSP00000498499.1	Q2NKJ3-1
CTC1	ENST00000932859.1		c.2162G>C	p.Gly721Ala	missense	Exon 13 of 23	ENSP00000602918.1
CTC1	ENST00000968384.1		c.2162G>C	p.Gly721Ala	missense	Exon 13 of 23	ENSP00000638443.1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2063

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0248

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0131

AC:

2189

AN:

166804

AF XY:

0.0136

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00834

Gnomad ASJ exome

AF:

0.00930

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0186

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.0161

AC:

22145

AN:

1377678

Hom.:

237

Cov.:

AF XY:

0.0160

AC XY:

10868

AN XY:

677954

show subpopulations

African (AFR)

AF:

0.00519

AC:

158

AN:

30424

American (AMR)

AF:

0.00947

AC:

280

AN:

29552

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

240

AN:

20258

East Asian (EAS)

AF:

0.00

AC:

AN:

38988

South Asian (SAS)

AF:

0.00484

AC:

345

AN:

71238

European-Finnish (FIN)

AF:

0.0206

AC:

1029

AN:

49932

Middle Eastern (MID)

AF:

0.0593

AC:

317

AN:

5342

European-Non Finnish (NFE)

AF:

0.0176

AC:

18930

AN:

1075244

Other (OTH)

AF:

0.0149

AC:

846

AN:

56700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1264

2529

3793

5058

6322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

704

1408

2112

2816

3520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0135

AC:

2060

AN:

152246

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

1007

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00429

AC:

178

AN:

41540

American (AMR)

AF:

0.0140

AC:

214

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.00353

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0248

AC:

263

AN:

10610

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0190

AC:

1291

AN:

68002

Other (OTH)

AF:

0.0142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

110

220

330

440

550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0122

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.00410

AC:

ESP6500EA

AF:

0.0192

AC:

159

ExAC

AF:

0.0127

AC:

1512

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cerebroretinal microangiopathy with calcifications and cysts 1 (2)

Dyskeratosis congenita (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.050

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.19

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PhyloP100

-0.93

PrimateAI

Benign

0.23

PROVEAN

Benign

0.16

REVEL

Benign

0.24

Sift

Benign

0.79

Sift4G

Benign

0.67

Polyphen

0.016

Vest4

0.026

MPC

0.14

ClinPred

0.0018

GERP RS

-2.9

Varity_R

0.034

gMVP

0.15

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over