X-154776813-CAAGAAGAAG-CAAGAAG

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]

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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
DKC1NM_001363.5 linkc.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
DKC1ENST00000369550.10 linkc.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.:
0
Cov.:
22
AF XY:
0.000990
AC XY:
32
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.:
0
AF XY:
0.00116
AC XY:
51
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.:
0
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.:
0
Cov.:
22
AF XY:
0.000989
AC XY:
32
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
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 24, 2015
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 16, 2015
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:3
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 03, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dyskeratosis congenita Benign:3
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2016
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 24, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

DKC1-related disorder Benign:1
Jan 13, 2020
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
Jan 23, 2019
Johns Hopkins Genomics, Johns Hopkins University
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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.

Other links and lift over

dbSNP: rs782576893; hg19: chrX-154005088; API