17-8229445-T-C

Variant names:

• chr17-8229445-T-C
• rs3826543
• NM_025099.6:c.3013A>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.3013A>G​(p.Ile1005Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,610,584 control chromosomes in the GnomAD database, including 509,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1005F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.77 (45623 hom., cov: 32)
  • Exomes 𝑓: 0.79 (463418 hom.)
• Consequence: CTC1 NM_025099.6 missense, splice_region
• Scores: Splicing: ADA: 0.00005087
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.940
• Publications: 40 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.250869E-7).
• BP6: Variant 17-8229445-T-C is Benign according to our data. Variant chr17-8229445-T-C is described in ClinVar as Benign. ClinVar VariationId is 128861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.814 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.3013A>G	p.Ile1005Val	missense splice_region	Exon 19 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.3013A>G	p.Ile1005Val	missense splice_region	Exon 19 of 21	NP_001397996.1	J3KSZ1
	CTC1	NR_046431.2		n.2928A>G		splice_region non_coding_transcript_exon	Exon 19 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.3013A>G	p.Ile1005Val	missense splice_region	Exon 19 of 23	ENSP00000498499.1	Q2NKJ3-1
	CTC1	ENST00000932859.1		c.3013A>G	p.Ile1005Val	missense splice_region	Exon 19 of 23	ENSP00000602918.1
	CTC1	ENST00000581729.2	TSL:3	c.3013A>G	p.Ile1005Val	missense splice_region	Exon 19 of 21	ENSP00000462720.2	J3KSZ1

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116828 AN: 151964 Hom.: 45581 Cov.: 32

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.855

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.820

Gnomad OTH AF: 0.744

GnomAD2 exomes AF: 0.737 AC: 183172 AN: 248494 AF XY: 0.748

Gnomad AFR exome AF: 0.761

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.667

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.855

Gnomad NFE exome AF: 0.819

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.791 AC: 1154369 AN: 1458502 Hom.: 463418 Cov.: 40 AF XY: 0.792 AC XY: 575053 AN XY: 725762

African (AFR) AF: 0.756 AC: 25237 AN: 33382

American (AMR) AF: 0.564 AC: 25208 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 17437 AN: 26098

East Asian (EAS) AF: 0.347 AC: 13780 AN: 39680

South Asian (SAS) AF: 0.781 AC: 67259 AN: 86174

European-Finnish (FIN) AF: 0.857 AC: 45707 AN: 53342

Middle Eastern (MID) AF: 0.681 AC: 3892 AN: 5716

European-Non Finnish (NFE) AF: 0.820 AC: 909871 AN: 1109188

Other (OTH) AF: 0.763 AC: 45978 AN: 60262

GnomAD4 genome AF: 0.769 AC: 116921 AN: 152082 Hom.: 45623 Cov.: 32 AF XY: 0.766 AC XY: 56981 AN XY: 74354

African (AFR) AF: 0.765 AC: 31735 AN: 41474

American (AMR) AF: 0.657 AC: 10025 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 2258 AN: 3470

East Asian (EAS) AF: 0.376 AC: 1938 AN: 5152

South Asian (SAS) AF: 0.776 AC: 3741 AN: 4820

European-Finnish (FIN) AF: 0.855 AC: 9054 AN: 10592

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.820 AC: 55731 AN: 67988

Other (OTH) AF: 0.741 AC: 1567 AN: 2114

Alfa AF: 0.788 Hom.: 160841

Bravo AF: 0.750

TwinsUK AF: 0.835 AC: 3098

ALSPAC AF: 0.820 AC: 3160

ESP6500AA AF: 0.773 AC: 3039

ESP6500EA AF: 0.814 AC: 6762

ExAC AF: 0.750 AC: 90589

Asia WGS AF: 0.619 AC: 2156 AN: 3478

EpiCase AF: 0.793

EpiControl AF: 0.796

ClinVar

ClinVar submissions

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	0.065
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.015
DANN	Benign	0.13
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.086	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.7	N
PhyloP100		-0.94
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.097
ClinPred		0.0032	T
GERP RS		-3.3
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.072
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0040
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: rs3826543; hg19: chr17-8132763; COSMIC: COSV59853841; COSMIC: COSV59853841;