X-154763183-C-T

Variant names:

• chrX-154763183-C-T
• rs2728530
• NM_001363.5:c.16+202C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001363.5(DKC1):​c.16+202C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 110,652 control chromosomes in the GnomAD database, including 9,987 homozygotes. There are 14,529 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.44 (9987 hom., 14529 hem., cov: 23)
• Consequence: DKC1 NM_001363.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.190
• Publications: 3 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-154763183-C-T is Benign according to our data. Variant chrX-154763183-C-T is described in ClinVar as [Benign]. Clinvar id is 1295610.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.16+202C>T		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+202C>T		intron_variant	Intron 1 of 14	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes AF: 0.443 AC: 49010 AN: 110597 Hom.: 9988 Cov.: 23

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.521

Gnomad NFE AF: 0.608

Gnomad OTH AF: 0.466

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.443 AC: 48995 AN: 110652 Hom.: 9987 Cov.: 23 AF XY: 0.441 AC XY: 14529 AN XY: 32936

African (AFR) AF: 0.0865 AC: 2654 AN: 30699

American (AMR) AF: 0.389 AC: 4141 AN: 10646

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1433 AN: 2619

East Asian (EAS) AF: 0.763 AC: 2620 AN: 3434

South Asian (SAS) AF: 0.361 AC: 948 AN: 2624

European-Finnish (FIN) AF: 0.695 AC: 4036 AN: 5806

Middle Eastern (MID) AF: 0.535 AC: 115 AN: 215

European-Non Finnish (NFE) AF: 0.608 AC: 31895 AN: 52451

Other (OTH) AF: 0.463 AC: 693 AN: 1497

Alfa AF: 0.477 Hom.: 4088

Bravo AF: 0.416

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.2
DANN	Benign	0.80
PhyloP100		0.19
PromoterAI		-0.0066	Neutral
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2728530; hg19: chrX-153991458; COSMIC: COSV65777032; COSMIC: COSV65777032;