NM_001363.5:c.1461C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001363.5(DKC1):c.1461C>T(p.Ala487Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,193,942 control chromosomes in the GnomAD database, including 1,815 homozygotes. There are 22,899 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 273 hom., 2194 hem., cov: 23)

Exomes 𝑓: 0.061 ( 1542 hom. 20705 hem. )

Consequence

DKC1
NM_001363.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.809

Publications

8 publications found

Variant links:

Genes affected

DKC1 (HGNC:2890): (dyskerin pseudouridine synthase 1) This gene functions in two distinct complexes. It plays an active role in telomerase stabilization and maintenance, as well as recognition of snoRNAs containing H/ACA sequences which provides stability during biogenesis and assembly into H/ACA small nucleolar RNA ribonucleoproteins (snoRNPs). This gene is highly conserved and widely expressed, and may play additional roles in nucleo-cytoplasmic shuttling, DNA damage response, and cell adhesion. Mutations have been associated with X-linked dyskeratosis congenita. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

DKC1 Gene-Disease associations (from GenCC):

DKC1-related disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
dyskeratosis congenita, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DKC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant X-154776309-C-T is Benign according to our data. Variant chrX-154776309-C-T is described in ClinVar as Benign. ClinVar VariationId is 128896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.809 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5 link	c.1461C>T	p.Ala487Ala	synonymous_variant	Exon 14 of 15	ENST00000369550.10	NP_001354.1	O60832-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10 link	c.1461C>T	p.Ala487Ala	synonymous_variant	Exon 14 of 15	1	NM_001363.5	ENSP00000358563.5		O60832-1

Frequencies

GnomAD3 genomes

AF:

0.0722

AC:

8075

AN:

111859

Hom.:

273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.0272

Gnomad EAS

AF:

0.0363

Gnomad SAS

AF:

0.00443

Gnomad FIN

AF:

0.0392

Gnomad MID

AF:

0.0294

Gnomad NFE

AF:

0.0628

Gnomad OTH

AF:

0.0596

GnomAD2 exomes

AF:

0.0522

AC:

7864

AN:

150590

AF XY:

0.0464

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.0323

Gnomad ASJ exome

AF:

0.0286

Gnomad EAS exome

AF:

0.0450

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.0649

Gnomad OTH exome

AF:

0.0512

GnomAD4 exome

AF:

0.0610

AC:

66020

AN:

1082032

Hom.:

1542

Cov.:

AF XY:

0.0588

AC XY:

20705

AN XY:

352114

show subpopulations

African (AFR)

AF:

0.123

AC:

3201

AN:

26023

American (AMR)

AF:

0.0341

AC:

1105

AN:

32391

Ashkenazi Jewish (ASJ)

AF:

0.0286

AC:

546

AN:

19121

East Asian (EAS)

AF:

0.0467

AC:

1372

AN:

29368

South Asian (SAS)

AF:

0.00556

AC:

291

AN:

52314

European-Finnish (FIN)

AF:

0.0463

AC:

1839

AN:

39678

Middle Eastern (MID)

AF:

0.0127

AC:

AN:

4098

European-Non Finnish (NFE)

AF:

0.0661

AC:

55058

AN:

833533

Other (OTH)

AF:

0.0562

AC:

2556

AN:

45506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

2425

4850

7276

9701

12126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2140

4280

6420

8560

10700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0722

AC:

8084

AN:

111910

Hom.:

273

Cov.:

AF XY:

0.0643

AC XY:

2194

AN XY:

34140

show subpopulations

African (AFR)

AF:

0.120

AC:

3683

AN:

30725

American (AMR)

AF:

0.0484

AC:

515

AN:

10642

Ashkenazi Jewish (ASJ)

AF:

0.0272

AC:

AN:

2648

East Asian (EAS)

AF:

0.0369

AC:

131

AN:

3547

South Asian (SAS)

AF:

0.00444

AC:

AN:

2702

European-Finnish (FIN)

AF:

0.0392

AC:

240

AN:

6117

Middle Eastern (MID)

AF:

0.0323

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0628

AC:

3335

AN:

53115

Other (OTH)

AF:

0.0588

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

283

566

850

1133

1416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0687

Hom.:

2281

Bravo

AF:

0.0768

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 06, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Benign:2

Nov 24, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.0

(source)

DANN

Benign

0.74

PhyloP100

-0.81

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over