rs8078338

Variant names:

• chr17-8225842-A-G
• rs8078338
• NM_025099.6:c.*2338T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_025099.6(CTC1):​c.*2338T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 150,772 control chromosomes in the GnomAD database, including 13,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13582 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: CTC1 NM_025099.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.566
• Publications: 11 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

ENSG00000305852 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-8225842-A-G is Benign according to our data. Variant chr17-8225842-A-G is described in ClinVar as [Benign]. Clinvar id is 325991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6	c.*2338T>C		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.*2338T>C		3_prime_UTR_variant	Exon 23 of 23		NM_025099.6	ENSP00000498499.1
ENSG00000305852	ENST00000813477.1	n.444A>G		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000305852	ENST00000813476.1	n.*9A>G		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61076 AN: 150698 Hom.: 13588 Cov.: 31

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.355

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.425

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.405 AC: 61064 AN: 150772 Hom.: 13582 Cov.: 31 AF XY: 0.408 AC XY: 30015 AN XY: 73592

African (AFR) AF: 0.242 AC: 9974 AN: 41240

American (AMR) AF: 0.319 AC: 4823 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1198 AN: 3470

East Asian (EAS) AF: 0.230 AC: 1189 AN: 5176

South Asian (SAS) AF: 0.449 AC: 2155 AN: 4804

European-Finnish (FIN) AF: 0.611 AC: 6060 AN: 9926

Middle Eastern (MID) AF: 0.349 AC: 99 AN: 284

European-Non Finnish (NFE) AF: 0.506 AC: 34266 AN: 67750

Other (OTH) AF: 0.421 AC: 878 AN: 2086

Alfa AF: 0.457 Hom.: 23031

Bravo AF: 0.376

Asia WGS AF: 0.307 AC: 1072 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita Benign:1

Jan 13, 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	-0.85
CADD	Benign	0.78
DANN	Benign	0.64
PhyloP100		-0.57

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: rs8078338; hg19: chr17-8129160; COSMIC: COSV59852613; COSMIC: COSV59852613;