17-8228251-G-C

Variant names:

• chr17-8228251-G-C
• rs199473682
• NM_025099.6:c.3583C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025099.6(CTC1):​c.3583C>G​(p.Arg1195Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1195Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 1 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):

• dyskeratosis congenita

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• cerebroretinal microangiopathy with calcifications and cysts 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Coats plus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20366585).

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.3583C>G	p.Arg1195Gly	missense	Exon 23 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.3352C>G	p.Arg1118Gly	missense	Exon 21 of 21	NP_001397996.1	J3KSZ1
	CTC1	NR_046431.2		n.3433C>G		non_coding_transcript_exon	Exon 22 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.3583C>G	p.Arg1195Gly	missense	Exon 23 of 23	ENSP00000498499.1	Q2NKJ3-1
	CTC1	ENST00000932859.1		c.3550C>G	p.Arg1184Gly	missense	Exon 23 of 23	ENSP00000602918.1
	CTC1	ENST00000968384.1		c.3487C>G	p.Arg1163Gly	missense	Exon 23 of 23	ENSP00000638443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249524 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.39
Sift	Benign	0.037	D
Sift4G	Uncertain	0.025	D
Polyphen		0.63	P
Vest4		0.30
MutPred		0.48		Loss of methylation at R1195 (P = 0.0118)
MVP		0.54
MPC		0.29
ClinPred		0.22	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.55
Mutation Taster		=59/41	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: rs199473682; hg19: chr17-8131569;