Genetic Variant DKC1:p.His68Gln (chrX-154765939-C-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1PM1PM2PM5PP3_Strong

The NM_001363.5(DKC1):c.204C>A(p.His68Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H68R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

DKC1
NM_001363.5 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.228

Publications

9 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DKC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS1

Transcript NM_001363.5 (DKC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001363.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154765938-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 446380.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DKC1	NM_001363.5	MANE Select	c.204C>A	p.His68Gln	missense	Exon 4 of 15	NP_001354.1	O60832-1
DKC1	NM_001142463.3		c.204C>A	p.His68Gln	missense	Exon 4 of 15	NP_001135935.1	A0A8Q3SIY6
DKC1	NM_001288747.2		c.204C>A	p.His68Gln	missense	Exon 4 of 14	NP_001275676.1	O60832-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DKC1	ENST00000369550.10	TSL:1 MANE Select	c.204C>A	p.His68Gln	missense	Exon 4 of 15	ENSP00000358563.5	O60832-1
DKC1	ENST00000620277.4	TSL:1	n.428C>A		non_coding_transcript_exon	Exon 4 of 14
DKC1	ENST00000953351.1		c.204C>A	p.His68Gln	missense	Exon 4 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dyskeratosis congenita, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.022

MutationAssessor

Pathogenic

3.7

PhyloP100

0.23

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

0.87

Vest4

0.71

MutPred

0.85

Loss of glycosylation at T66 (P = 0.0823)

MVP

0.99

MPC

2.4

ClinPred

1.0

GERP RS

-0.0036

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.93

gMVP

0.98

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over