rs3027238

Variant names:

• chr17-8231743-T-C
• rs3027238
• NM_025099.6:c.2458A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025099.6(CTC1):​c.2458A>G​(p.Ile820Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,614,034 control chromosomes in the GnomAD database, including 747,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I820T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.95 (68212 hom., cov: 31)
  • Exomes 𝑓: 0.96 (679060 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.260
• Publications: 38 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.026743E-7).
• BP6: Variant 17-8231743-T-C is Benign according to our data. Variant chr17-8231743-T-C is described in ClinVar as Benign. ClinVar VariationId is 128860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

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.2458A>G	p.Ile820Val	missense	Exon 14 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.2458A>G	p.Ile820Val	missense	Exon 14 of 21	NP_001397996.1
	CTC1	NR_046431.2		n.2373A>G		non_coding_transcript_exon	Exon 14 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.2458A>G	p.Ile820Val	missense	Exon 14 of 23	ENSP00000498499.1
	CTC1	ENST00000932859.1		c.2458A>G	p.Ile820Val	missense	Exon 14 of 23	ENSP00000602918.1
	CTC1	ENST00000968384.1		c.2458A>G	p.Ile820Val	missense	Exon 14 of 23	ENSP00000638443.1

Frequencies

GnomAD3 genomes AF: 0.946 AC: 143894 AN: 152144 Hom.: 68160 Cov.: 31

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.886

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.940

Gnomad FIN AF: 0.993

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.969

Gnomad OTH AF: 0.937

GnomAD2 exomes AF: 0.947 AC: 236367 AN: 249528 AF XY: 0.950

Gnomad AFR exome AF: 0.923

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.859

Gnomad EAS exome AF: 0.992

Gnomad FIN exome AF: 0.991

Gnomad NFE exome AF: 0.970

Gnomad OTH exome AF: 0.948

GnomAD4 exome AF: 0.963 AC: 1408345 AN: 1461772 Hom.: 679060 Cov.: 50 AF XY: 0.963 AC XY: 700130 AN XY: 727186

African (AFR) AF: 0.919 AC: 30768 AN: 33476

American (AMR) AF: 0.871 AC: 38963 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.862 AC: 22538 AN: 26134

East Asian (EAS) AF: 0.990 AC: 39312 AN: 39700

South Asian (SAS) AF: 0.934 AC: 80580 AN: 86250

European-Finnish (FIN) AF: 0.990 AC: 52897 AN: 53420

Middle Eastern (MID) AF: 0.901 AC: 5195 AN: 5768

European-Non Finnish (NFE) AF: 0.972 AC: 1080607 AN: 1111914

Other (OTH) AF: 0.952 AC: 57485 AN: 60388

GnomAD4 genome AF: 0.946 AC: 144004 AN: 152262 Hom.: 68212 Cov.: 31 AF XY: 0.945 AC XY: 70324 AN XY: 74428

African (AFR) AF: 0.923 AC: 38321 AN: 41526

American (AMR) AF: 0.886 AC: 13548 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2948 AN: 3472

East Asian (EAS) AF: 0.989 AC: 5124 AN: 5182

South Asian (SAS) AF: 0.941 AC: 4541 AN: 4826

European-Finnish (FIN) AF: 0.993 AC: 10540 AN: 10614

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.969 AC: 65906 AN: 68026

Other (OTH) AF: 0.934 AC: 1975 AN: 2114

Alfa AF: 0.956 Hom.: 210792

Bravo AF: 0.939

TwinsUK AF: 0.974 AC: 3610

ALSPAC AF: 0.977 AC: 3765

ESP6500AA AF: 0.929 AC: 3604

ESP6500EA AF: 0.964 AC: 7996

ExAC AF: 0.951 AC: 114876

Asia WGS AF: 0.944 AC: 3283 AN: 3478

EpiCase AF: 0.963

EpiControl AF: 0.964

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Cerebroretinal microangiopathy with calcifications and cysts 1 (2)
-	-	2	Dyskeratosis congenita (2)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.2
DANN	Benign	0.20
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.26
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.098
ClinPred		0.00029	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.095
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3027238; hg19: chr17-8135061; COSMIC: COSV107326235; COSMIC: COSV107326235;