rs138725914

Variant names:

• chr17-8237504-A-G
• rs138725914
• NM_025099.6:c.663T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_025099.6(CTC1):​c.663T>C​(p.Gly221Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,613,566 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 29)
  • Exomes 𝑓: 0.00078 (4 hom.)
• Consequence: CTC1 NM_025099.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.392
• Publications: 3 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-8237504-A-G is Benign according to our data. Variant chr17-8237504-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 326083.
• BP7: Synonymous conserved (PhyloP=-0.392 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000783 (1144/1461858) while in subpopulation EAS AF = 0.0108 (427/39698). AF 95% confidence interval is 0.00991. There are 4 homozygotes in GnomAdExome4. There are 540 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	NM_025099.6	MANE Select	c.663T>C	p.Gly221Gly	synonymous	Exon 5 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.663T>C	p.Gly221Gly	synonymous	Exon 5 of 21	NP_001397996.1
	CTC1	NR_046431.2		n.668-90T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.663T>C	p.Gly221Gly	synonymous	Exon 5 of 23	ENSP00000498499.1
	CTC1	ENST00000581729.2	TSL:3	c.663T>C	p.Gly221Gly	synonymous	Exon 5 of 21	ENSP00000462720.2
	CTC1	ENST00000580299.2	TSL:5	c.663T>C	p.Gly221Gly	synonymous	Exon 5 of 21	ENSP00000462607.2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 151592 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00542

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00133 AC: 331 AN: 249502 AF XY: 0.00113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00239

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000783 AC: 1144 AN: 1461858 Hom.: 4 Cov.: 31 AF XY: 0.000743 AC XY: 540 AN XY: 727218

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: 0.0108 AC: 427 AN: 39698

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86256

European-Finnish (FIN) AF: 0.0104 AC: 557 AN: 53414

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

European-Non Finnish (NFE) AF: 0.0000845 AC: 94 AN: 1111990

Other (OTH) AF: 0.000894 AC: 54 AN: 60394

GnomAD4 genome AF: 0.00113 AC: 171 AN: 151708 Hom.: 1 Cov.: 29 AF XY: 0.00148 AC XY: 110 AN XY: 74134

African (AFR) AF: 0.00 AC: 0 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00543 AC: 28 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67882

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000151

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Dyskeratosis congenita (2)
-	-	1	Cerebroretinal microangiopathy with calcifications and cysts 1 (1)
-	-	1	CTC1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.9
DANN	Benign	0.81
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138725914; hg19: chr17-8140822;