17-8227905-C-T

Variant names:

• chr17-8227905-C-T
• rs3027246
• NM_025099.6:c.*275G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025099.6(CTC1):​c.*275G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 347,944 control chromosomes in the GnomAD database, including 5,889 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2183 hom., cov: 31)
  • Exomes 𝑓: 0.18 (3706 hom.)
• Consequence: CTC1 NM_025099.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.246
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6	c.*275G>A		3_prime_UTR_variant	Exon 23 of 23	ENST00000651323.1	NP_079375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1	c.*275G>A		3_prime_UTR_variant	Exon 23 of 23		NM_025099.6	ENSP00000498499.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22879 AN: 151986 Hom.: 2183 Cov.: 31

Gnomad AFR AF: 0.0476

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0385

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.176 AC: 34378 AN: 195840 Hom.: 3706 Cov.: 0 AF XY: 0.174 AC XY: 17820 AN XY: 102190

African (AFR) AF: 0.0429 AC: 308 AN: 7172

American (AMR) AF: 0.116 AC: 1166 AN: 10012

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 1322 AN: 6276

East Asian (EAS) AF: 0.0266 AC: 376 AN: 14120

South Asian (SAS) AF: 0.110 AC: 2086 AN: 19004

European-Finnish (FIN) AF: 0.148 AC: 1336 AN: 9038

Middle Eastern (MID) AF: 0.187 AC: 163 AN: 870

European-Non Finnish (NFE) AF: 0.217 AC: 25607 AN: 117890

Other (OTH) AF: 0.176 AC: 2014 AN: 11458

GnomAD4 genome AF: 0.150 AC: 22878 AN: 152104 Hom.: 2183 Cov.: 31 AF XY: 0.145 AC XY: 10812 AN XY: 74362

African (AFR) AF: 0.0475 AC: 1972 AN: 41520

American (AMR) AF: 0.135 AC: 2063 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 767 AN: 3468

East Asian (EAS) AF: 0.0384 AC: 198 AN: 5160

South Asian (SAS) AF: 0.110 AC: 528 AN: 4816

European-Finnish (FIN) AF: 0.151 AC: 1603 AN: 10590

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15205 AN: 67962

Other (OTH) AF: 0.144 AC: 304 AN: 2106

Alfa AF: 0.196 Hom.: 4169

Bravo AF: 0.146

Asia WGS AF: 0.0700 AC: 244 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dyskeratosis congenita Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.61
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs3027246; hg19: chr17-8131223; COSMIC: COSV59855122; COSMIC: COSV59855122;