chr17-8234545-C-T

Variant names:

• chr17-8234545-C-T
• rs78320653
• NM_025099.6:c.1728G>A

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.1728G>A​(p.Pro576Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,574,920 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P576P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: CTC1 NM_025099.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.471
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-8234545-C-T is Benign according to our data. Variant chr17-8234545-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 326079.
• BP7: Synonymous conserved (PhyloP=-0.471 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1728G>A	p.Pro576Pro	synonymous	Exon 10 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.1728G>A	p.Pro576Pro	synonymous	Exon 10 of 21	NP_001397996.1
	CTC1	NR_046431.2		n.1643G>A		non_coding_transcript_exon	Exon 10 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.1728G>A	p.Pro576Pro	synonymous	Exon 10 of 23	ENSP00000498499.1
	CTC1	ENST00000932859.1		c.1728G>A	p.Pro576Pro	synonymous	Exon 10 of 23	ENSP00000602918.1
	CTC1	ENST00000968384.1		c.1728G>A	p.Pro576Pro	synonymous	Exon 10 of 23	ENSP00000638443.1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00132 AC: 245 AN: 186210 AF XY: 0.00129

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.00168

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000119

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.000408

GnomAD4 exome AF: 0.00190 AC: 2700 AN: 1422648 Hom.: 6 Cov.: 34 AF XY: 0.00183 AC XY: 1289 AN XY: 703974

African (AFR) AF: 0.000214 AC: 7 AN: 32752

American (AMR) AF: 0.00129 AC: 49 AN: 37910

Ashkenazi Jewish (ASJ) AF: 0.00181 AC: 46 AN: 25402

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37766

South Asian (SAS) AF: 0.000209 AC: 17 AN: 81514

European-Finnish (FIN) AF: 0.000510 AC: 26 AN: 50972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00226 AC: 2463 AN: 1091644

Other (OTH) AF: 0.00154 AC: 91 AN: 58962

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74468

African (AFR) AF: 0.000313 AC: 13 AN: 41556

American (AMR) AF: 0.00307 AC: 47 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00238 AC: 162 AN: 67998

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00153

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Dyskeratosis congenita (3)
-	1	1	not provided (2)
-	-	1	Cerebroretinal microangiopathy with calcifications and cysts 1 (1)
-	-	1	CTC1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.3
DANN	Benign	0.42
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs78320653; hg19: chr17-8137863; COSMIC: COSV59853284; COSMIC: COSV59853284;