rs146700772

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP6_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

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3B:8O:1

Conservation

PhyloP100: 3.60

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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.

BP6

Variant X-154769233-A-C is Benign according to our data. Variant chrX-154769233-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 38952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154769233-A-C is described in Lovd as [Pathogenic].

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5 link	c.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
DKC1	ENST00000369550.10 link	c.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:

AN:

111255

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

33435

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

GnomAD3 exomes

AF:

0.000267

AC:

AN:

183531

Hom.:

AF XY:

0.000235

AC XY:

AN XY:

67959

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 SAS 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.:

Cov.:

AF XY:

0.000358

AC XY:

130

AN XY:

363019

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.000666

Gnomad4 NFE exome

AF:

0.000415

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.000270

AC:

AN:

111306

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

33496

show subpopulations

Gnomad4 AFR

AF:

0.0000327

Gnomad4 AMR

AF:

0.000287

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000373

Gnomad4 FIN

AF:

0.000512

Gnomad4 NFE

AF:

0.000396

Gnomad4 OTH

AF:

0.000661

Alfa

AF:

0.000444

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:3Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DKC1: PP2, BS2 -

Dyskeratosis congenita

Benign:3

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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. -

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 -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance: 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

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;D;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.50

D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

3.1

M;M;.

PrimateAI

Uncertain

0.63

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

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.95

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over