rs121912297

Variant names:

• chrX-154765931-A-G
• rs121912297
• NM_001363.5:c.196A>G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001363.5(DKC1):​c.196A>G​(p.Thr66Ala) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:2
• Conservation: PhyloP100: 8.88

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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant X-154765931-A-G is Pathogenic according to our data. Variant chrX-154765931-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154765931-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.196A>G	p.Thr66Ala	missense_variant	Exon 4 of 15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.196A>G	p.Thr66Ala	missense_variant	Exon 4 of 15	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, X-linked Other:2

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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not provided Pathogenic:1

Jan 02, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that p.(T66A) leads to lowered levels of rRNA seudouridylation as well as an increase in cell apoptosis (PMID: 11851894, 23707062); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22117216, 9888995, 23707062, 21228398, 30577491, 10364516, 38272871, 36496180, 30202881, 11851894) -

Dyskeratosis congenita Pathogenic:1

Mar 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 66 of the DKC1 protein (p.Thr66Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dyskeratosis congenita (PMID: 768476, 9888995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38946). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DKC1 protein function. Experimental studies have shown that this missense change affects DKC1 function (PMID: 10591218, 16690864, 18212040, 23707062, 26571381, 30202881). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	.;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.9	M;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.4	.;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.010	.;D;D
Sift4G	Uncertain	0.034	D;D;D
Polyphen		0.29	.;B;.
Vest4		0.76
MutPred		0.73		Loss of glycosylation at T66 (P = 0.0375);Loss of glycosylation at T66 (P = 0.0375);Loss of glycosylation at T66 (P = 0.0375);
MVP		1.0
MPC		2.2
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.58
gMVP		0.96

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: rs121912297; hg19: chrX-153994206;