rs2728534

Variant names:

• chrX-154768338-T-G
• rs2728534
• NM_001363.5:c.677T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001363.5(DKC1):​c.677T>G​(p.Ile226Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 21)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64
• Publications: 1 publications found

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]

SNORA36A (HGNC:32628): (small nucleolar RNA, H/ACA box 36A) Biosynthesis of stable cellular RNAs such as tRNAs, rRNAs, snRNAs, and snoRNAs is aided by covalent nucleotide modification after transcription. The modified nucleotides are involved in correct RNA folding, establishment of correct RNA-RNA and RNA-protein interactions, and in the correct function of mature RNAs. The RNA encoded by this gene is thought to mediate the pseudouridylation of residues U105 and U1244 of 18S rRNA. [provided by RefSeq, Feb 2009]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKC1	NM_001363.5	c.677T>G	p.Ile226Ser	missense_variant	Exon 8 of 15	ENST00000369550.10	NP_001354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKC1	ENST00000369550.10	c.677T>G	p.Ile226Ser	missense_variant	Exon 8 of 15	1	NM_001363.5	ENSP00000358563.5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H
PhyloP100		7.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.4	.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.81		Gain of phosphorylation at T224 (P = 0.1213);Gain of phosphorylation at T224 (P = 0.1213);
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2728534; hg19: chrX-153996613;