rs121912306

chrX-154765949-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_001363.5(DKC1):c.214C>T(p.Leu72Phe) variant causes a missense change involving the alteration of a non-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. L72Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.91

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001363.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154765949-CT-TA is described in ClinVar as [Pathogenic]. Clinvar id is 11585.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, DKC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKC1	NM_001363.5	c.214C>T	p.Leu72Phe	missense_variant	4/15	ENST00000369550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKC1	ENST00000369550.10	c.214C>T	p.Leu72Phe	missense_variant	4/15	1	NM_001363.5	P2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Dyskeratosis congenita, X-linked Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	22
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.57	.;P;.
Vest4		0.66
MutPred		0.74		Loss of catalytic residue at L72 (P = 0.0863);Loss of catalytic residue at L72 (P = 0.0863);Loss of catalytic residue at L72 (P = 0.0863);
MVP		0.99
MPC		2.5
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.78
gMVP		0.95

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: rs121912306; hg19: chrX-153994224;