rs199473682

Variant names:

• chr17-8228251-G-A
• rs199473682
• NM_025099.6:c.3583C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-8228251-G-A
• chr17-8228251-G-C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The ENST00000651323.1(CTC1):​c.3583C>T​(p.Arg1195*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CTC1 ENST00000651323.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.29
• Publications: 1 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):

• cerebroretinal microangiopathy with calcifications and cysts 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• dyskeratosis congenita

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Coats plus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0194 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 17-8228251-G-A is Pathogenic according to our data. Variant chr17-8228251-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000651323.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	NM_025099.6	MANE Select	c.3583C>T	p.Arg1195*	stop_gained	Exon 23 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.3352C>T	p.Arg1118*	stop_gained	Exon 21 of 21	NP_001397996.1
	CTC1	NR_046431.2		n.3433C>T		non_coding_transcript_exon	Exon 22 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.3583C>T	p.Arg1195*	stop_gained	Exon 23 of 23	ENSP00000498499.1
	CTC1	ENST00000581729.2	TSL:3	c.3352C>T	p.Arg1118*	stop_gained	Exon 21 of 21	ENSP00000462720.2
	CTC1	ENST00000580299.2	TSL:5	c.3319C>T	p.Arg1107*	stop_gained	Exon 21 of 21	ENSP00000462607.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	0.053
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.17	N
PhyloP100		1.3
Vest4		0.52
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=9/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473682; hg19: chr17-8131569;