rs121912302

Variant names:

• chrX-154765480-G-A
• rs121912302
• NM_001363.5:c.121G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001363.5(DKC1):​c.121G>A​(p.Glu41Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:2
• Conservation: PhyloP100: 7.18
• Publications: 5 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001363.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.121G>A	p.Glu41Lys	missense_variant	Exon 3 of 15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.121G>A	p.Glu41Lys	missense_variant	Exon 3 of 15	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita, X-linked Other:2

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dyskeratosis congenita Uncertain:1

May 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect DKC1 function (PMID: 22117216). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 38940). This missense change has been observed in individual(s) with dyskeratosis congenita (PMID: 10364516). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 41 of the DKC1 protein (p.Glu41Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	.;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.8	M;M;.
PhyloP100		7.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	.;N;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.010	.;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.032	.;B;.
Vest4		0.76
MutPred		0.71		Gain of MoRF binding (P = 0.0355);Gain of MoRF binding (P = 0.0355);Gain of MoRF binding (P = 0.0355);
MVP		1.0
MPC		1.5
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.47
gMVP		0.87
Mutation Taster		=53/47	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.050		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: rs121912302; hg19: chrX-153993755;