17-8235251-C-G

Variant names:

• chr17-8235251-C-G
• rs62624978
• NM_025099.6:c.1241G>C

Variant summary

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

The ENST00000651323.1(CTC1):​c.1241G>C​(p.Gly414Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,613,968 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. G414E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 32)
  • Exomes 𝑓: 0.016 (240 hom.)
• Consequence: CTC1 ENST00000651323.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.01
• Publications: 6 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=0.008434802).
• BP6: Variant 17-8235251-C-G is Benign according to our data. Variant chr17-8235251-C-G is described in ClinVar as Benign. ClinVar VariationId is 241577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000651323.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	NM_025099.6	MANE Select	c.1241G>C	p.Gly414Ala	missense	Exon 8 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.1241G>C	p.Gly414Ala	missense	Exon 8 of 21	NP_001397996.1
	CTC1	NR_046431.2		n.1156G>C		non_coding_transcript_exon	Exon 8 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.1241G>C	p.Gly414Ala	missense	Exon 8 of 23	ENSP00000498499.1
	CTC1	ENST00000581729.2	TSL:3	c.1241G>C	p.Gly414Ala	missense	Exon 8 of 21	ENSP00000462720.2
	CTC1	ENST00000580299.2	TSL:5	c.1241G>C	p.Gly414Ala	missense	Exon 8 of 21	ENSP00000462607.2

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2056 AN: 152186 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0129 AC: 3214 AN: 248690 AF XY: 0.0132

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00847

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0158 AC: 23050 AN: 1461664 Hom.: 240 Cov.: 33 AF XY: 0.0157 AC XY: 11404 AN XY: 727122

African (AFR) AF: 0.00496 AC: 166 AN: 33478

American (AMR) AF: 0.00932 AC: 417 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 320 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00480 AC: 414 AN: 86256

European-Finnish (FIN) AF: 0.0206 AC: 1097 AN: 53322

Middle Eastern (MID) AF: 0.0578 AC: 333 AN: 5764

European-Non Finnish (NFE) AF: 0.0175 AC: 19411 AN: 1111892

Other (OTH) AF: 0.0148 AC: 892 AN: 60394

GnomAD4 genome AF: 0.0135 AC: 2053 AN: 152304 Hom.: 18 Cov.: 32 AF XY: 0.0135 AC XY: 1004 AN XY: 74462

African (AFR) AF: 0.00423 AC: 176 AN: 41568

American (AMR) AF: 0.0138 AC: 211 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4824

European-Finnish (FIN) AF: 0.0246 AC: 261 AN: 10608

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0190 AC: 1291 AN: 68022

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0142 Hom.: 16

Bravo AF: 0.0122

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00463 AC: 19

ESP6500EA AF: 0.0203 AC: 171

ExAC AF: 0.0134 AC: 1620

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0192

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0084	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.26
Sift	Benign	0.63	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.17
MPC		0.59
ClinPred		0.034	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.42
Mutation Taster		=94/6	polymorphism

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: rs62624978; hg19: chr17-8138569; COSMIC: COSV59853570; COSMIC: COSV59853570;