X-154776813-CAAGAAGAAGAAG-CAAGAAGAAGAAGAAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001363.5(DKC1):c.1512_1514dupGAA(p.Lys505dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0043 in 1,194,697 control chromosomes in the GnomAD database, including 18 homozygotes. There are 891 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., 130 hem., cov: 22)

Exomes 𝑓: 0.0043 ( 12 hom. 761 hem. )

Consequence

DKC1
NM_001363.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.30

Publications

12 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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001363.5

BP6

Variant X-154776813-C-CAAG is Benign according to our data. Variant chrX-154776813-C-CAAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00449 (493/109827) while in subpopulation SAS AF = 0.03 (74/2468). AF 95% confidence interval is 0.0245. There are 6 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 493 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5 link	c.1512_1514dupGAA	p.Lys505dup	disruptive_inframe_insertion	Exon 15 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.1512_1514dupGAA	p.Lys505dup	disruptive_inframe_insertion	Exon 15 of 15	1	NM_001363.5	ENSP00000358563.5		O60832-1

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

490

AN:

109780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000761

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00764

Gnomad ASJ

AF:

0.0191

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.0291

Gnomad FIN

AF:

0.000875

Gnomad MID

AF:

0.0426

Gnomad NFE

AF:

0.00454

Gnomad OTH

AF:

0.00821

GnomAD2 exomes

AF:

0.00777

AC:

997

AN:

128377

AF XY:

0.00386

show subpopulations

Gnomad AFR exome

AF:

0.000626

Gnomad AMR exome

AF:

0.00618

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00549

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.00428

AC:

4646

AN:

1084870

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

761

AN XY:

355106

show subpopulations

African (AFR)

AF:

0.000765

AC:

AN:

26127

American (AMR)

AF:

0.00411

AC:

143

AN:

34756

Ashkenazi Jewish (ASJ)

AF:

0.0183

AC:

348

AN:

19002

East Asian (EAS)

AF:

0.000235

AC:

AN:

29811

South Asian (SAS)

AF:

0.0224

AC:

1162

AN:

51923

European-Finnish (FIN)

AF:

0.000802

AC:

AN:

39917

Middle Eastern (MID)

AF:

0.0376

AC:

153

AN:

4066

European-Non Finnish (NFE)

AF:

0.00298

AC:

2488

AN:

833735

Other (OTH)

AF:

0.00643

AC:

293

AN:

45533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

214

428

641

855

1069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<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:

0.00449

AC:

493

AN:

109827

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

130

AN XY:

32439

show subpopulations

African (AFR)

AF:

0.000760

AC:

AN:

30278

American (AMR)

AF:

0.00763

AC:

AN:

10360

Ashkenazi Jewish (ASJ)

AF:

0.0191

AC:

AN:

2624

East Asian (EAS)

AF:

0.000283

AC:

AN:

3537

South Asian (SAS)

AF:

0.0300

AC:

AN:

2468

European-Finnish (FIN)

AF:

0.000875

AC:

AN:

5716

Middle Eastern (MID)

AF:

0.0372

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00454

AC:

238

AN:

52471

Other (OTH)

AF:

0.0101

AC:

AN:

1480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00477

Hom.:

Bravo

AF:

0.00509

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita, X-linked

Benign:3

Oct 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 07, 2017

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. -

Sep 10, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 14, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.3

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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