rs200440641

Variant names:

• chr17-8234553-G-A
• rs200440641
• NM_025099.6:c.1720C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_025099.6(CTC1):​c.1720C>T​(p.Pro574Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,584,618 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P574L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 3.16
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010326743).
• BP6: Variant 17-8234553-G-A is Benign according to our data. Variant chr17-8234553-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 412531.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.1720C>T	p.Pro574Ser	missense	Exon 10 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.1720C>T	p.Pro574Ser	missense	Exon 10 of 21	NP_001397996.1
	CTC1	NR_046431.2		n.1635C>T		non_coding_transcript_exon	Exon 10 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.1720C>T	p.Pro574Ser	missense	Exon 10 of 23	ENSP00000498499.1
	CTC1	ENST00000932859.1		c.1720C>T	p.Pro574Ser	missense	Exon 10 of 23	ENSP00000602918.1
	CTC1	ENST00000968384.1		c.1720C>T	p.Pro574Ser	missense	Exon 10 of 23	ENSP00000638443.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00120 AC: 240 AN: 199770 AF XY: 0.00117

Gnomad AFR exome AF: 0.000345

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000515

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.00157 AC: 2248 AN: 1432262 Hom.: 2 Cov.: 34 AF XY: 0.00153 AC XY: 1088 AN XY: 709700

African (AFR) AF: 0.000212 AC: 7 AN: 33018

American (AMR) AF: 0.00191 AC: 75 AN: 39352

Ashkenazi Jewish (ASJ) AF: 0.00368 AC: 94 AN: 25532

East Asian (EAS) AF: 0.00 AC: 0 AN: 38406

South Asian (SAS) AF: 0.000339 AC: 28 AN: 82502

European-Finnish (FIN) AF: 0.000563 AC: 29 AN: 51552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00175 AC: 1918 AN: 1096816

Other (OTH) AF: 0.00163 AC: 97 AN: 59348

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74514

African (AFR) AF: 0.000264 AC: 11 AN: 41594

American (AMR) AF: 0.00157 AC: 24 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.00204 AC: 17

ExAC AF: 0.000871 AC: 105

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Dyskeratosis congenita (3)
-	1	1	Cerebroretinal microangiopathy with calcifications and cysts 1 (2)
-	1	-	CTC1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.079	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.25	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.13
MVP		0.78
MPC		0.57
ClinPred		0.035	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.54
Mutation Taster		=95/5	polymorphism

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: rs200440641; hg19: chr17-8137871;