rs146700772

chrX-154769233-A-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3 B:7 O:1
• Conservation: PhyloP100: 3.60

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DKC1
• 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 GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKC1	NM_001363.5	c.838A>C	p.Ser280Arg	missense_variant	9/15	ENST00000369550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKC1	ENST00000369550.10	c.838A>C	p.Ser280Arg	missense_variant	9/15	1	NM_001363.5	P2

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 30 AN: 111255 Hom.: 0 Cov.: 23 AF XY: 0.000239 AC XY: 8 AN XY: 33435

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: 49 AN: 183531 Hom.: 0 AF XY: 0.000235 AC XY: 16 AN XY: 67959

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.: 0 Cov.: 30 AF XY: 0.000358 AC XY: 130 AN XY: 363019

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: 30 AN: 111306 Hom.: 0 Cov.: 23 AF XY: 0.000239 AC XY: 8 AN XY: 33496

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.: 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:3 Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	DKC1: PP2, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Dyskeratosis congenita Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 26, 2022	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:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

DKC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2021

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
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;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.63	T
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

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

Other links and lift over

dbSNP: rs146700772; hg19: chrX-153997508;