chrX-154770792-C-T

Variant names:

• chrX-154770792-C-T
• rs121912290
• NM_001363.5:c.949C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001363.5(DKC1):​c.949C>T​(p.Leu317Phe) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L317V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 4.61
• Publications: 6 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]

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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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, 0.935
• PP5: Variant X-154770792-C-T is Pathogenic according to our data. Variant chrX-154770792-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 38957.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	NM_001363.5	MANE Select	c.949C>T	p.Leu317Phe	missense	Exon 10 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.949C>T	p.Leu317Phe	missense	Exon 10 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.949C>T	p.Leu317Phe	missense	Exon 10 of 14	NP_001275676.1	O60832-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	ENST00000369550.10	TSL:1 MANE Select	c.949C>T	p.Leu317Phe	missense	Exon 10 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.1173C>T		non_coding_transcript_exon	Exon 10 of 14
	DKC1	ENST00000953351.1		c.985C>T	p.Leu329Phe	missense	Exon 10 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Dyskeratosis congenita (1)
-	-	-	Dyskeratosis congenita, X-linked (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		4.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		0.72	P
Vest4		0.75
MutPred		0.84		Gain of methylation at K314 (P = 0.1051)
MVP		0.99
MPC		2.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.98
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs121912290; hg19: chrX-153999067;