rs78870822

chr17-8238579-C-Gchr17-8238579-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025099.6(CTC1):c.248G>C(p.Ser83Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 1,613,822 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts 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. S83N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (81 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.39

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010699332).
• BP6: Variant 17-8238579-C-G is Benign according to our data. Variant chr17-8238579-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 210795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8238579-C-G is described in Lovd as [Benign]. Variant chr17-8238579-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00708 (1078/152292) while in subpopulation NFE AF= 0.00838 (570/68016). AF 95% confidence interval is 0.00781. There are 11 homozygotes in gnomad4. There are 605 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTC1	NM_025099.6	c.248G>C	p.Ser83Thr	missense_variant	3/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1	c.248G>C	p.Ser83Thr	missense_variant	3/23		NM_025099.6	P1

Frequencies

GnomAD3 genomes AF: 0.00708 AC: 1078 AN: 152174 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00838

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00867 AC: 2157 AN: 248724 Hom.: 25 AF XY: 0.00873 AC XY: 1178 AN XY: 134918

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00949

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000393

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00777 AC: 11353 AN: 1461530 Hom.: 81 Cov.: 31 AF XY: 0.00758 AC XY: 5514 AN XY: 727066

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.00946

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.00781

Gnomad4 OTH exome AF: 0.00681

GnomAD4 genome AF: 0.00708 AC: 1078 AN: 152292 Hom.: 11 Cov.: 31 AF XY: 0.00813 AC XY: 605 AN XY: 74458

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0362

Gnomad4 NFE AF: 0.00838

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00701 Hom.: 2

Bravo AF: 0.00468

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000971 AC: 4

ESP6500EA AF: 0.00903 AC: 76

ExAC AF: 0.00902 AC: 1091

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00752

EpiControl AF: 0.00830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2020	This variant is associated with the following publications: (PMID: 26344056) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CTC1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 20, 2022	Variant summary: CTC1 c.248G>C (p.Ser83Thr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0087 in 248724 control chromosomes, including 25 homozygotes (gnomAD). The variant occurs predominantly at a frequency of 0.01 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CTC1 causing Cerebroretinal Microangiopathy With Calcifications And Cysts 1 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.248G>C in individuals affected with Cerebroretinal Microangiopathy With Calcifications And Cysts 1 and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign and five as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dyskeratosis congenita Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cerebroretinal microangiopathy with calcifications and cysts 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 12, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.86
MPC		0.54
ClinPred		0.011	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs78870822; hg19: chr17-8141897; COSMIC: COSV99044186; COSMIC: COSV99044186;