NM_001363.5:c.16+24_16+39delCGTGCTAACTCCGGGC

Variant names:

• chrX-154762997-TTCCGGGCCGTGCTAAC-T
• NM_001363.5:c.16+24_16+39delCGTGCTAACTCCGGGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001363.5(DKC1):​c.16+24_16+39delCGTGCTAACTCCGGGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,062,877 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: DKC1 NM_001363.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.546
• Publications: 0 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: 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

ENSG00000307948 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant X-154762997-TTCCGGGCCGTGCTAAC-T is Benign according to our data. Variant chrX-154762997-TTCCGGGCCGTGCTAAC-T is described in ClinVar as [Likely_benign]. Clinvar id is 1629821.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.16+24_16+39delCGTGCTAACTCCGGGC		intron_variant	Intron 1 of 14	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.16+17_16+32delTCCGGGCCGTGCTAAC		intron_variant	Intron 1 of 14	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000188 AC: 2 AN: 1062877 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 345659

⚠️ 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: 25475

American (AMR) AF: 0.00 AC: 0 AN: 29634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18743

East Asian (EAS) AF: 0.00 AC: 0 AN: 28128

South Asian (SAS) AF: 0.00 AC: 0 AN: 50435

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4092

European-Non Finnish (NFE) AF: 0.00000243 AC: 2 AN: 823785

Other (OTH) AF: 0.00 AC: 0 AN: 44717

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita Benign:1

Jan 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.55

Splicing

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

Other links and lift over

hg19: chrX-153991272;