rs199473674

Variant names:

• chr17-8237439-GCTTT-G
• rs199473674
• NM_025099.6:c.724_727delAAAG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_025099.6(CTC1):​c.724_727delAAAG​(p.Lys242LeufsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: CTC1 NM_025099.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 2.20
• 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-8237439-GCTTT-G is Pathogenic according to our data. Variant chr17-8237439-GCTTT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.724_727delAAAG	p.Lys242LeufsTer41	frameshift	Exon 5 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.724_727delAAAG	p.Lys242LeufsTer41	frameshift	Exon 5 of 21	NP_001397996.1	J3KSZ1
	CTC1	NR_046431.2		n.668-29_668-26delAAAG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.724_727delAAAG	p.Lys242LeufsTer41	frameshift	Exon 5 of 23	ENSP00000498499.1	Q2NKJ3-1
	CTC1	ENST00000932859.1		c.724_727delAAAG	p.Lys242LeufsTer41	frameshift	Exon 5 of 23	ENSP00000602918.1
	CTC1	ENST00000968384.1		c.724_727delAAAG	p.Lys242LeufsTer41	frameshift	Exon 5 of 23	ENSP00000638443.1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151992 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000200 AC: 50 AN: 249584 AF XY: 0.000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000288 AC: 421 AN: 1461468 Hom.: 0 AF XY: 0.000259 AC XY: 188 AN XY: 727058

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000334 AC: 371 AN: 1111626

Other (OTH) AF: 0.000431 AC: 26 AN: 60380

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151992 Hom.: 0 Cov.: 29 AF XY: 0.000175 AC XY: 13 AN XY: 74240

African (AFR) AF: 0.0000725 AC: 3 AN: 41362

American (AMR) AF: 0.000328 AC: 5 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68002

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000321

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Cerebroretinal microangiopathy with calcifications and cysts 1 (10)
3	-	-	not provided (3)
1	-	-	CTC1-related disorder (1)
1	-	-	Dyskeratosis congenita (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199473674; hg19: chr17-8140757;