rs200643329

Variant names:

• chr17-8231467-T-C
• rs200643329
• NM_025099.6:c.2478A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_025099.6(CTC1):​c.2478A>G​(p.Thr826Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,603,758 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (5 hom.)
• Consequence: CTC1 NM_025099.6 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -1.96
• 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):

• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 17-8231467-T-C is Benign according to our data. Variant chr17-8231467-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241581.
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.2478A>G	p.Thr826Thr	splice_region synonymous	Exon 15 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.2478A>G	p.Thr826Thr	splice_region synonymous	Exon 15 of 21	NP_001397996.1	J3KSZ1
	CTC1	NR_046431.2		n.2393A>G		splice_region non_coding_transcript_exon	Exon 15 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.2478A>G	p.Thr826Thr	splice_region synonymous	Exon 15 of 23	ENSP00000498499.1	Q2NKJ3-1
	CTC1	ENST00000932859.1		c.2478A>G	p.Thr826Thr	splice_region synonymous	Exon 15 of 23	ENSP00000602918.1
	CTC1	ENST00000968384.1		c.2478A>G	p.Thr826Thr	splice_region synonymous	Exon 15 of 23	ENSP00000638443.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00135 AC: 328 AN: 243054 AF XY: 0.00131

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000453

Gnomad OTH exome AF: 0.00325

GnomAD4 exome AF: 0.000765 AC: 1110 AN: 1451462 Hom.: 5 Cov.: 32 AF XY: 0.000754 AC XY: 544 AN XY: 721116

African (AFR) AF: 0.000875 AC: 29 AN: 33140

American (AMR) AF: 0.00186 AC: 81 AN: 43440

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 444 AN: 25678

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85134

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53292

Middle Eastern (MID) AF: 0.00293 AC: 14 AN: 4772

European-Non Finnish (NFE) AF: 0.000362 AC: 401 AN: 1106644

Other (OTH) AF: 0.00232 AC: 139 AN: 59850

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74474

African (AFR) AF: 0.00103 AC: 43 AN: 41560

American (AMR) AF: 0.00366 AC: 56 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68026

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00164

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Cerebroretinal microangiopathy with calcifications and cysts 1 (2)
-	1	1	Dyskeratosis congenita (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.099
DANN	Benign	0.37
PhyloP100		-2.0
Mutation Taster		=98/2	polymorphism

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: rs200643329; hg19: chr17-8134785;