rs78390421

chr17-8236110-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025099.6(CTC1):c.1025A>G(p.Asp342Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,614,216 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D342E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (54 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.91

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034905076).
• BP6: Variant 17-8236110-T-C is Benign according to our data. Variant chr17-8236110-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 326082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2062/152330) while in subpopulation AFR AF= 0.0473 (1966/41570). AF 95% confidence interval is 0.0456. There are 50 homozygotes in gnomad4. There are 975 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTC1	NM_025099.6	c.1025A>G	p.Asp342Gly	missense_variant	6/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1	c.1025A>G	p.Asp342Gly	missense_variant	6/23		NM_025099.6	P1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2059 AN: 152212 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00323 AC: 805 AN: 249412 Hom.: 20 AF XY: 0.00247 AC XY: 334 AN XY: 135338

Gnomad AFR exome AF: 0.0464

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000884

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00140 AC: 2051 AN: 1461886 Hom.: 54 Cov.: 37 AF XY: 0.00121 AC XY: 877 AN XY: 727246

Gnomad4 AFR exome AF: 0.0511

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000827

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.0135 AC: 2062 AN: 152330 Hom.: 50 Cov.: 33 AF XY: 0.0131 AC XY: 975 AN XY: 74488

Gnomad4 AFR AF: 0.0473

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00242 Hom.: 8

Bravo AF: 0.0155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0424 AC: 164

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00398 AC: 481

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Cerebroretinal microangiopathy with calcifications and cysts 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.57	P
Vest4		0.35
MVP		0.54
MPC		0.47
ClinPred		0.018	T
GERP RS		3.6
Varity_R		0.11
gMVP		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

Publications

LitVar

Other links and lift over

dbSNP: rs78390421; hg19: chr17-8139428;