dbSNP rs2728534: DKC1:p.Ile226Ser (chrX-154768338-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.64

Publications

1 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 links:

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]

SNORA36A links:

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ACMG classification

Classification was made for transcript

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

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.677T>G	p.Ile226Ser	missense	Exon 8 of 15	NP_001354.1	O60832-1
DKC1	NM_001142463.3		c.677T>G	p.Ile226Ser	missense	Exon 8 of 15	NP_001135935.1	A0A8Q3SIY6
DKC1	NM_001288747.2		c.677T>G	p.Ile226Ser	missense	Exon 8 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.677T>G	p.Ile226Ser	missense	Exon 8 of 15	ENSP00000358563.5	O60832-1
DKC1	ENST00000620277.4	TSL:1	n.901T>G		non_coding_transcript_exon	Exon 8 of 14
DKC1	ENST00000953351.1		c.713T>G	p.Ile238Ser	missense	Exon 8 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.70

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

PhyloP100

7.6

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.93

MutPred

0.81

Gain of phosphorylation at T224 (P = 0.1213)

MVP

1.0

MPC

3.1

ClinPred

1.0

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

(source)

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

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