X-154769233-A-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001363.5(DKC1):​c.838A>C​(p.Ser280Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000357 in 1,208,959 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 138 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., 8 hem., cov: 23)
Exomes 𝑓: 0.00037 ( 0 hom. 130 hem. )

Consequence

DKC1
NM_001363.5 missense

Scores

6
8
3

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3B:9O:1

Conservation

PhyloP100: 3.60

Publications

8 publications found
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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6
Variant X-154769233-A-C is Benign according to our data. Variant chrX-154769233-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 30 XL,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DKC1NM_001363.5 linkc.838A>C p.Ser280Arg missense_variant Exon 9 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.838A>C p.Ser280Arg missense_variant Exon 9 of 15 1 NM_001363.5 ENSP00000358563.5 O60832-1

Frequencies

GnomAD3 genomes
AF:
0.000270
AC:
30
AN:
111255
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.0000327
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000288
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000372
Gnomad FIN
AF:
0.000512
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000396
Gnomad OTH
AF:
0.000670
GnomAD2 exomes
AF:
0.000267
AC:
49
AN:
183531
AF XY:
0.000235
show subpopulations
Gnomad AFR exome
AF:
0.0000760
Gnomad AMR exome
AF:
0.000109
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000437
Gnomad NFE exome
AF:
0.000439
Gnomad OTH exome
AF:
0.000441
GnomAD4 exome
AF:
0.000366
AC:
402
AN:
1097653
Hom.:
0
Cov.:
30
AF XY:
0.000358
AC XY:
130
AN XY:
363019
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26397
American (AMR)
AF:
0.0000852
AC:
3
AN:
35206
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19381
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30200
South Asian (SAS)
AF:
0.0000185
AC:
1
AN:
54141
European-Finnish (FIN)
AF:
0.000666
AC:
27
AN:
40534
Middle Eastern (MID)
AF:
0.000484
AC:
2
AN:
4130
European-Non Finnish (NFE)
AF:
0.000415
AC:
349
AN:
841581
Other (OTH)
AF:
0.000434
AC:
20
AN:
46083
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
16
32
48
64
80
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000270
AC:
30
AN:
111306
Hom.:
0
Cov.:
23
AF XY:
0.000239
AC XY:
8
AN XY:
33496
show subpopulations
African (AFR)
AF:
0.0000327
AC:
1
AN:
30609
American (AMR)
AF:
0.000287
AC:
3
AN:
10437
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2645
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3574
South Asian (SAS)
AF:
0.000373
AC:
1
AN:
2678
European-Finnish (FIN)
AF:
0.000512
AC:
3
AN:
5864
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
217
European-Non Finnish (NFE)
AF:
0.000396
AC:
21
AN:
53084
Other (OTH)
AF:
0.000661
AC:
1
AN:
1512
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000393
Hom.:
17
Bravo
AF:
0.000200
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.000288
AC:
35
EpiCase
AF:
0.000327
EpiControl
AF:
0.000474

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:3Benign:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:2
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

DKC1: PP2, BS2 -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Dyskeratosis congenita Benign:3
Aug 26, 2022
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nov 15, 2021
Sema4, Sema4
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Dec 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dyskeratosis congenita, X-linked Benign:2Other:1
Feb 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of X-linked recessive dyskeratosis congenita (MIM#305000). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 07, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

not specified Benign:1
Feb 16, 2025
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

DKC1-related disorder Benign:1
May 21, 2021
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.37
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
.;D;.
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Uncertain
0.50
D;D;D
MetaSVM
Uncertain
0.35
D
MutationAssessor
Pathogenic
3.1
M;M;.
PhyloP100
3.6
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-3.6
.;D;D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.023
.;D;D
Sift4G
Benign
0.070
T;D;T
Polyphen
0.17
.;B;.
Vest4
0.48
MutPred
0.71
Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);.;
MVP
1.0
MPC
1.5
ClinPred
0.13
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.95
Mutation Taster
=41/59
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

Publications

Other links and lift over

dbSNP: rs146700772; hg19: chrX-153997508; API