rs137854491
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_001363.5(DKC1):c.91C>A(p.Gln31Lys) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q31E) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 23)
Consequence
DKC1
NM_001363.5 missense
NM_001363.5 missense
Scores
6
3
4
Clinical Significance
Conservation
PhyloP100: 7.17
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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, 0.77
PP5
?
Variant X-154765450-C-A is Pathogenic according to our data. Variant chrX-154765450-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11594.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154765450-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DKC1 | NM_001363.5 | c.91C>A | p.Gln31Lys | missense_variant | 3/15 | ENST00000369550.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DKC1 | ENST00000369550.10 | c.91C>A | p.Gln31Lys | 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: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Dyskeratosis congenita, X-linked Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2005 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T
Polyphen
0.10
.;B;.
Vest4
MutPred
Gain of ubiquitination at Q31 (P = 0.0045);Gain of ubiquitination at Q31 (P = 0.0045);Gain of ubiquitination at Q31 (P = 0.0045);
MVP
MPC
1.8
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