dbSNP rs782576893: DKC1:p.Lys502_Lys505del (chrX-154776813-CAAGAAGAAGAAG-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

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

The NM_001363.5(DKC1):c.1503_1514delGAAGAAGAAGAA(p.Lys502_Lys505del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000092 in 1,086,846 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K501K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

DKC1
NM_001363.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.53

Publications

0 publications found

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 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DKC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP3

Nonframeshift variant in repetitive region in NM_001363.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5 link	c.1503_1514delGAAGAAGAAGAA	p.Lys502_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.1503_1514delGAAGAAGAAGAA	p.Lys502_Lys505del	disruptive_inframe_deletion	Exon 15 of 15	1	NM_001363.5	ENSP00000358563.5		O60832-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.20e-7

AC:

AN:

1086846

Hom.:

AF XY:

0.00

AC XY:

AN XY:

356918

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26137

American (AMR)

AF:

0.00

AC:

AN:

34778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19106

East Asian (EAS)

AF:

0.00

AC:

AN:

29815

South Asian (SAS)

AF:

0.00

AC:

AN:

52810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4089

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

834570

Other (OTH)

AF:

0.00

AC:

AN:

45607

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.5

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over