rs12946837

Variant names:

• chr17-8247860-G-A
• rs12946837
• NM_025099.6:c.33+144C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-8247860-G-A
• chr17-8247860-G-C

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.33+144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 747,678 control chromosomes in the GnomAD database, including 1,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (220 hom., cov: 31)
  • Exomes 𝑓: 0.057 (1270 hom.)
• Consequence: CTC1 NM_025099.6 intron
• Scores: Splicing: ADA: 0.00008497
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0200
• Publications: 3 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]

PFAS (HGNC:8863): (phosphoribosylformylglycinamidine synthase) Purines are necessary for many cellular processes, including DNA replication, transcription, and energy metabolism. Ten enzymatic steps are required to synthesize inosine monophosphate (IMP) in the de novo pathway of purine biosynthesis. The enzyme encoded by this gene catalyzes the fourth step of IMP biosynthesis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-8247860-G-A is Benign according to our data. Variant chr17-8247860-G-A is described in ClinVar as [Benign]. Clinvar id is 1227785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6	c.33+144C>T		intron_variant	Intron 1 of 22	ENST00000651323.1	NP_079375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1	c.33+144C>T		intron_variant	Intron 1 of 22		NM_025099.6	ENSP00000498499.1

Frequencies

GnomAD3 genomes AF: 0.0465 AC: 7083 AN: 152172 Hom.: 220 Cov.: 31

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.0937

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0710

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0573 AC: 34105 AN: 595388 Hom.: 1270 Cov.: 8 AF XY: 0.0552 AC XY: 17367 AN XY: 314466

African (AFR) AF: 0.0116 AC: 179 AN: 15424

American (AMR) AF: 0.0262 AC: 722 AN: 27594

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 322 AN: 17644

East Asian (EAS) AF: 0.0000946 AC: 3 AN: 31714

South Asian (SAS) AF: 0.0126 AC: 729 AN: 57854

European-Finnish (FIN) AF: 0.0880 AC: 4137 AN: 47032

Middle Eastern (MID) AF: 0.00697 AC: 27 AN: 3872

European-Non Finnish (NFE) AF: 0.0726 AC: 26396 AN: 363406

Other (OTH) AF: 0.0515 AC: 1590 AN: 30848

GnomAD4 genome AF: 0.0465 AC: 7081 AN: 152290 Hom.: 220 Cov.: 31 AF XY: 0.0464 AC XY: 3458 AN XY: 74462

African (AFR) AF: 0.0120 AC: 498 AN: 41570

American (AMR) AF: 0.0328 AC: 502 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4830

European-Finnish (FIN) AF: 0.0937 AC: 994 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0710 AC: 4828 AN: 68012

Other (OTH) AF: 0.0435 AC: 92 AN: 2114

Alfa AF: 0.0604 Hom.: 86

Bravo AF: 0.0417

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.3
DANN	Benign	0.88
PhyloP100		0.020
PromoterAI		0.037	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000085
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.010		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: rs12946837; hg19: chr17-8151178;