dbSNP rs121912303: DKC1:p.Ala2Gly (chrX-154762970-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_001363.5(DKC1):c.5C>G(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000936 in 1,068,811 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

DKC1
NM_001363.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.78

Publications

0 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

DKC1 links:

ENSG00000307948 (HGNC:):

ENSG00000307948 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity DKC1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154762970-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38951.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 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.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 15	1	NM_001363.5	ENSP00000358563.5		O60832-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.36e-7

AC:

AN:

1068811

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

347707

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25728

American (AMR)

AF:

0.00

AC:

AN:

30776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18805

East Asian (EAS)

AF:

0.00

AC:

AN:

28574

South Asian (SAS)

AF:

0.00

AC:

AN:

50839

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38163

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4099

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

826919

Other (OTH)

AF:

0.00

AC:

AN:

44908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;T;.

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.53

T;T;T

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

1.8

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.85

.;N;N

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

.;D;D

Sift4G

Uncertain

0.021

D;D;D

Polyphen

0.99

.;D;.

Vest4

0.39

MutPred

0.45

Gain of relative solvent accessibility (P = 0.0024);Gain of relative solvent accessibility (P = 0.0024);Gain of relative solvent accessibility (P = 0.0024);

MVP

0.93

MPC

1.4

ClinPred

0.86

GERP RS

3.9

PromoterAI

-0.62

Under-expression

(source)

Varity_R

0.44

gMVP

0.65

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over