17-8238579-C-G

Variant names:

• chr17-8238579-C-G
• rs78870822
• NM_025099.6:c.248G>C

Variant summary

Our verdict is Benign. The variant received -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:15
• Conservation: PhyloP100: 3.39
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 210795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	NM_025099.6	MANE Select	c.248G>C	p.Ser83Thr	missense	Exon 3 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.248G>C	p.Ser83Thr	missense	Exon 3 of 21	NP_001397996.1	J3KSZ1
	CTC1	NR_046431.2		n.268G>C		non_coding_transcript_exon	Exon 3 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.248G>C	p.Ser83Thr	missense	Exon 3 of 23	ENSP00000498499.1	Q2NKJ3-1
	CTC1	ENST00000932859.1		c.248G>C	p.Ser83Thr	missense	Exon 3 of 23	ENSP00000602918.1
	CTC1	ENST00000968384.1		c.248G>C	p.Ser83Thr	missense	Exon 3 of 23	ENSP00000638443.1

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

GnomAD2 exomes AF: 0.00867 AC: 2157 AN: 248724 AF XY: 0.00873

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 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

African (AFR) AF: 0.00102 AC: 34 AN: 33478

American (AMR) AF: 0.00289 AC: 129 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00946 AC: 247 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86230

European-Finnish (FIN) AF: 0.0340 AC: 1814 AN: 53390

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00781 AC: 8685 AN: 1111780

Other (OTH) AF: 0.00681 AC: 411 AN: 60380

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

African (AFR) AF: 0.00101 AC: 42 AN: 41578

American (AMR) AF: 0.00288 AC: 44 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0362 AC: 384 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00838 AC: 570 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Cerebroretinal microangiopathy with calcifications and cysts 1 (3)
-	-	3	Dyskeratosis congenita (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.4
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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs78870822; hg19: chr17-8141897; COSMIC: COSV99044186; COSMIC: COSV99044186;