chrX-154776813-CAAGAAGAAG-C

Variant names:

• chrX-154776813-CAAGAAGAAG-C
• rs782576893
• NM_001363.5:c.1506_1514delGAAGAAGAA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001363.5(DKC1):​c.1506_1514delGAAGAAGAA​(p.Lys503_Lys505del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000125 in 1,196,609 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000013 (0 hom. 3 hem.)
• Consequence: DKC1 NM_001363.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53
• Publications: 12 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001363.5

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	NM_001363.5	MANE Select	c.1506_1514delGAAGAAGAA	p.Lys503_Lys505del	disruptive_inframe_deletion	Exon 15 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.1491_1499delGAAGAAGAA	p.Lys498_Lys500del	disruptive_inframe_deletion	Exon 15 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.*732_*740delGAAGAAGAA		3_prime_UTR	Exon 14 of 14	NP_001275676.1	O60832-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	ENST00000369550.10	TSL:1 MANE Select	c.1506_1514delGAAGAAGAA	p.Lys503_Lys505del	disruptive_inframe_deletion	Exon 15 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.2219_2227delGAAGAAGAA		non_coding_transcript_exon	Exon 14 of 14
	DKC1	ENST00000953351.1		c.1542_1550delGAAGAAGAA	p.Lys515_Lys517del	disruptive_inframe_deletion	Exon 15 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes AF: 0.00000911 AC: 1 AN: 109784 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000779 AC: 1 AN: 128377 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 14 AN: 1086825 Hom.: 0 AF XY: 0.00000841 AC XY: 3 AN XY: 356899

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26137

American (AMR) AF: 0.00 AC: 0 AN: 34776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19105

East Asian (EAS) AF: 0.00 AC: 0 AN: 29815

South Asian (SAS) AF: 0.00 AC: 0 AN: 52810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39933

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4089

European-Non Finnish (NFE) AF: 0.0000156 AC: 13 AN: 834554

Other (OTH) AF: 0.0000219 AC: 1 AN: 45606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000364320), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000911 AC: 1 AN: 109784 Hom.: 0 Cov.: 22 AF XY: 0.0000309 AC XY: 1 AN XY: 32386

African (AFR) AF: 0.00 AC: 0 AN: 30214

American (AMR) AF: 0.00 AC: 0 AN: 10347

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000191 AC: 1 AN: 52481

Other (OTH) AF: 0.00 AC: 0 AN: 1462

Alfa AF: 0.00 Hom.: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5

Splicing

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

Other links and lift over

dbSNP: rs782576893; hg19: chrX-154005088;