NM_025099.6:c.2923A>G

Variant names:

• chr17-8230304-T-C
• rs199473678
• NM_025099.6:c.2923A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3 PP5

The NM_025099.6(CTC1):​c.2923A>G​(p.Arg975Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,611,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000914256: Functional studies demonstrate that the p.Arg975Gly variant was found to reduce telomere association in vivo to 83% that of wild type, while other telomeric functions were found to be preserved, similar to those of wild type (Chen et al. 2013). Wang et al. (2018) showed that unlike wild type CTC1, the p.Arg975Gly variant failed to completely restore the chromosome abnormalities, RAD51 foci formation, and proliferation defects caused by CTC1 knockdown in cells and that the p.Arg975Gly variant significantly reduced CTC1 association to genomic fragile sites in response to replication stress indicating that this residue might be critical for RAD51 binding." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 2.18
• Publications: 9 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 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000914256: Functional studies demonstrate that the p.Arg975Gly variant was found to reduce telomere association in vivo to 83% that of wild type, while other telomeric functions were found to be preserved, similar to those of wild type (Chen et al. 2013). Wang et al. (2018) showed that unlike wild type CTC1, the p.Arg975Gly variant failed to completely restore the chromosome abnormalities, RAD51 foci formation, and proliferation defects caused by CTC1 knockdown in cells and that the p.Arg975Gly variant significantly reduced CTC1 association to genomic fragile sites in response to replication stress indicating that this residue might be critical for RAD51 binding.; SCV001783183: Published functional studies demonstrate a damaging effect with global genome instabilities under replication stress (Wang et al., 2018); SCV006325108: Functional studies indicate that the p.Arg975Gly amino acid change has a deleterious effect on CTC1 function (PMID: 24115768, PMID: 29481669).
• PP5: Variant 17-8230304-T-C is Pathogenic according to our data. Variant chr17-8230304-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 631531.

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.2923A>G	p.Arg975Gly	missense	Exon 17 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.2923A>G	p.Arg975Gly	missense	Exon 17 of 21	NP_001397996.1	J3KSZ1
	CTC1	NR_046431.2		n.2838A>G		non_coding_transcript_exon	Exon 17 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.2923A>G	p.Arg975Gly	missense	Exon 17 of 23	ENSP00000498499.1	Q2NKJ3-1
	CTC1	ENST00000932859.1		c.2923A>G	p.Arg975Gly	missense	Exon 17 of 23	ENSP00000602918.1
	CTC1	ENST00000968384.1		c.2923A>G	p.Arg975Gly	missense	Exon 17 of 23	ENSP00000638443.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000687 AC: 17 AN: 247296 AF XY: 0.0000671

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: 0.000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1459026 Hom.: 0 Cov.: 32 AF XY: 0.0000262 AC XY: 19 AN XY: 725810

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 85910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5122

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111008

Other (OTH) AF: 0.0000498 AC: 3 AN: 60208

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000458 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000579 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	1	-	Dyskeratosis congenita (3)
2	-	-	Cerebroretinal microangiopathy with calcifications and cysts 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.2
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.73	P
Vest4		0.40
MVP		0.66
MPC		0.38
ClinPred		0.42	T
GERP RS		3.2
PromoterAI		-0.0042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.64
gMVP		0.67
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199473678; hg19: chr17-8133622; COSMIC: COSV106102267; COSMIC: COSV106102267;