X-154776813-CAAGAAGAAG-CAAGAAGAAGAAG

Position:

• chrX-154776813-CAAGAAGAAG-CAAGAAGAAGAAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001363.5(DKC1):​c.1512_1514dup​(p.Lys504dup) variant causes a 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 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.30

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]

ACMG classification

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/exons	MANE	UniProt
DKC1	NM_001363.5	c.1512_1514dup	p.Lys504dup	inframe_insertion	15/15	ENST00000369550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKC1	ENST00000369550.10	c.1512_1514dup	p.Lys504dup	inframe_insertion	15/15	1	NM_001363.5	P2

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 490 AN: 109780 Hom.: 7 Cov.: 22 AF XY: 0.00395 AC XY: 128 AN XY: 32382

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.: 3 AF XY: 0.00386 AC XY: 169 AN XY: 43799

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.: 12 Cov.: 28 AF XY: 0.00214 AC XY: 761 AN XY: 355106

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.: 6 Cov.: 22 AF XY: 0.00401 AC XY: 130 AN XY: 32439

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, X-linked Benign:3

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

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Dyskeratosis congenita Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 10, 2020	- -
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. -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs782576893; hg19: chrX-154005088;