rs121912302
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_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
NM_001363.5 missense
Scores
7
5
1
Clinical Significance
Conservation
PhyloP100: 7.18
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 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, 4 uncertain in NM_001363.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DKC1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.896
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DKC1 | NM_001363.5 | c.121G>A | p.Glu41Lys | missense_variant | 3/15 | ENST00000369550.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DKC1 | ENST00000369550.10 | c.121G>A | p.Glu41Lys | missense_variant | 3/15 | 1 | NM_001363.5 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dyskeratosis congenita, X-linked Other:2
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Dyskeratosis congenita Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 04, 2022 | 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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dyskeratosis congenita (PMID: 10364516). ClinVar contains an entry for this variant (Variation ID: 38940). 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. Experimental studies have shown that this missense change does not substantially affect DKC1 function (PMID: 22117216). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
A
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D
Polyphen
0.032
.;B;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0355);Gain of MoRF binding (P = 0.0355);Gain of MoRF binding (P = 0.0355);
MVP
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at