dbSNP rs199422251: DKC1:p.Pro384Leu (chrX-154773245-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001363.5(DKC1):c.1151C>T(p.Pro384Leu) variant causes a missense change involving the alteration of a 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P384S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

DKC1
NM_001363.5 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 7.48

Publications

4 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), G2P, ClinGen
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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001363.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

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.1151C>T	p.Pro384Leu	missense	Exon 11 of 15	NP_001354.1	O60832-1
DKC1	NM_001142463.3		c.1151C>T	p.Pro384Leu	missense	Exon 11 of 15	NP_001135935.1	A0A8Q3SIY6
DKC1	NM_001288747.2		c.1151C>T	p.Pro384Leu	missense	Exon 11 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.1151C>T	p.Pro384Leu	missense	Exon 11 of 15	ENSP00000358563.5	O60832-1
DKC1	ENST00000620277.4	TSL:1	n.1375C>T		non_coding_transcript_exon	Exon 11 of 14
DKC1	ENST00000953351.1		c.1187C>T	p.Pro396Leu	missense	Exon 11 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1022814

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

301536

African (AFR)

AF:

0.00

AC:

AN:

25071

American (AMR)

AF:

0.00

AC:

AN:

35000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18799

East Asian (EAS)

AF:

0.00

AC:

AN:

29682

South Asian (SAS)

AF:

0.00

AC:

AN:

52258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3907

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

774490

Other (OTH)

AF:

0.00

AC:

AN:

43453

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

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

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.71

BayesDel_noAF

Pathogenic

0.78

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

PhyloP100

7.5

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-8.5

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.77

MutPred

0.64

Loss of glycosylation at P384 (P = 0.0195)

MVP

1.0

MPC

2.5

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.92

gMVP

0.95

Mutation Taster

=13/87

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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