rs1289430524

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001363.5(DKC1):​c.1346G>A​(p.Arg449Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,210,369 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

DKC1
NM_001363.5 missense

Scores

6
3
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.90
Variant links:
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 Uncertain_significance. Variant got 1 ACMG points.

PP2
Missense variant in the DKC1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. Gene score misZ: 3.3994 (above the threshold of 3.09). GenCC associations: The gene is linked to Hoyeraal-Hreidarsson syndrome, DKC1-related disorder, dyskeratosis congenita, X-linked, dyskeratosis congenita.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DKC1NM_001363.5 linkc.1346G>A p.Arg449Gln missense_variant Exon 14 of 15 ENST00000369550.10 NP_001354.1 O60832-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DKC1ENST00000369550.10 linkc.1346G>A p.Arg449Gln missense_variant Exon 14 of 15 1 NM_001363.5 ENSP00000358563.5 O60832-1

Frequencies

GnomAD3 genomes
AF:
0.00000889
AC:
1
AN:
112473
Hom.:
0
Cov.:
23
AF XY:
0.0000289
AC XY:
1
AN XY:
34631
show subpopulations
Gnomad AFR
AF:
0.0000323
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097896
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
1
AN XY:
363256
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000889
AC:
1
AN:
112473
Hom.:
0
Cov.:
23
AF XY:
0.0000289
AC XY:
1
AN XY:
34631
show subpopulations
Gnomad4 AFR
AF:
0.0000323
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inherited Immunodeficiency Diseases Uncertain:1
Uncertain significance, criteria provided, single submitterresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.29
T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
T
M_CAP
Pathogenic
0.66
D
MetaRNN
Uncertain
0.52
D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-0.69
N
REVEL
Uncertain
0.42
Sift
Benign
0.075
T
Sift4G
Benign
0.16
T
Polyphen
1.0
D
Vest4
0.35
MutPred
0.21
Gain of relative solvent accessibility (P = 0.0507);
MVP
0.96
MPC
0.30
ClinPred
0.89
D
GERP RS
5.0
Varity_R
0.18
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1289430524; hg19: chrX-154004469; API