X-154776813-CAAGAAGAAG-CAAGAAG

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_001363.5(DKC1):c.1512_1514delGAA(p.Lys505del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00286 in 1,059,870 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 353 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., 32 hem., cov: 22)

Exomes 𝑓: 0.0031 ( 0 hom. 321 hem. )

Consequence

DKC1
NM_001363.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 4.30

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant X-154776813-CAAG-C is Benign according to our data. Variant chrX-154776813-CAAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238951.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=3}. Variant chrX-154776813-CAAG-C is described in Lovd as [Likely_benign]. Variant chrX-154776813-CAAG-C is described in Lovd as [Benign]. Variant chrX-154776813-CAAG-C is described in Lovd as [Likely_benign]. Variant chrX-154776813-CAAG-C is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd4 at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5 link	c.1512_1514delGAA	p.Lys505del	disruptive_inframe_deletion	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_1514delGAA	p.Lys505del	disruptive_inframe_deletion	Exon 15 of 15	1	NM_001363.5	ENSP00000358563.5		O60832-1

Frequencies

GnomAD3 genomes

AF:

0.000958

AC:

105

AN:

109632

Hom.:

Cov.:

AF XY:

0.000990

AC XY:

AN XY:

32310

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00174

Gnomad ASJ

AF:

0.00686

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000177

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.00274

GnomAD3 exomes

AF:

0.00425

AC:

545

AN:

128377

Hom.:

AF XY:

0.00116

AC XY:

AN XY:

43799

show subpopulations

Gnomad AFR exome

AF:

0.00230

Gnomad AMR exome

AF:

0.00595

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.00303

Gnomad SAS exome

AF:

0.00149

Gnomad FIN exome

AF:

0.00188

Gnomad NFE exome

AF:

0.00398

Gnomad OTH exome

AF:

0.00776

GnomAD4 exome

AF:

0.00308

AC:

2930

AN:

950193

Hom.:

AF XY:

0.00104

AC XY:

321

AN XY:

308425

show subpopulations

Gnomad4 AFR exome

AF:

0.00292

Gnomad4 AMR exome

AF:

0.00466

Gnomad4 ASJ exome

AF:

0.0148

Gnomad4 EAS exome

AF:

0.00229

Gnomad4 SAS exome

AF:

0.000960

Gnomad4 FIN exome

AF:

0.00326

Gnomad4 NFE exome

AF:

0.00287

Gnomad4 OTH exome

AF:

0.00378

GnomAD4 genome

AF:

0.000957

AC:

105

AN:

109677

Hom.:

Cov.:

AF XY:

0.000989

AC XY:

AN XY:

32367

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.00174

Gnomad4 ASJ

AF:

0.00686

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000177

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.00271

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 24, 2015	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2024	- -

Dyskeratosis congenita

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2025	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

DKC1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dyskeratosis congenita, X-linked

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Jan 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over