X-154776813-CAAGAAGAAG-CAAGAAGAAGAAG

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_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

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 Benign. Variant got -16 ACMG points.

BP6

Variant X-154776813-C-CAAG is Benign according to our data. Variant chrX-154776813-C-CAAG is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 XL 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.:

AF XY:

0.00395

AC XY:

128

AN XY:

32382

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

GnomAD3 exomes

AF:

0.00777

AC:

997

AN:

128377

Hom.:

AF XY:

0.00386

AC XY:

169

AN XY:

43799

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 SAS exome

AF:

0.0301

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

Gnomad4 AFR exome

AF:

0.000765

Gnomad4 AMR exome

AF:

0.00411

Gnomad4 ASJ exome

AF:

0.0183

Gnomad4 EAS exome

AF:

0.000235

Gnomad4 SAS exome

AF:

0.0224

Gnomad4 FIN exome

AF:

0.000802

Gnomad4 NFE exome

AF:

0.00298

Gnomad4 OTH exome

AF:

0.00643

GnomAD4 genome

AF:

0.00449

AC:

493

AN:

109827

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

130

AN XY:

32439

show subpopulations

Gnomad4 AFR

AF:

0.000760

Gnomad4 AMR

AF:

0.00763

Gnomad4 ASJ

AF:

0.0191

Gnomad4 EAS

AF:

0.000283

Gnomad4 SAS

AF:

0.0300

Gnomad4 FIN

AF:

0.000875

Gnomad4 NFE

AF:

0.00454

Gnomad4 OTH

AF:

0.0101

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2024	- -
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)	-	- -

Dyskeratosis congenita, X-linked

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 21, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Dyskeratosis congenita

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2017	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	curation	Sema4, Sema4	Sep 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 14, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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