rs1370393255

Variant names:

• chrX-154776837-A-C
• rs1370393255
• NM_001363.5:c.1515A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-154776837-A-C
• chrX-154776837-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001363.5(DKC1):​c.1515A>C​(p.Lys505Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 111,408 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.411
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1515A>C	p.Lys505Asn	missense	Exon 15 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.1500A>C	p.Lys500Asn	missense	Exon 15 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.*741A>C		3_prime_UTR	Exon 14 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.1515A>C	p.Lys505Asn	missense	Exon 15 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.2228A>C		non_coding_transcript_exon	Exon 14 of 14
	DKC1	ENST00000953351.1		c.1551A>C	p.Lys517Asn	missense	Exon 15 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111408 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111408 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33642

African (AFR) AF: 0.00 AC: 0 AN: 30630

American (AMR) AF: 0.00 AC: 0 AN: 10525

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

South Asian (SAS) AF: 0.00 AC: 0 AN: 2544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52968

Other (OTH) AF: 0.00 AC: 0 AN: 1494

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Dyskeratosis congenita (1)
-	1	-	Dyskeratosis congenita, X-linked;C5829571:Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.41
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.43
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.22		Loss of methylation at K505 (P = 0.032)
MVP		0.97
MPC		0.48
ClinPred		0.94	D
GERP RS		4.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.40
gMVP		0.12
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1370393255; hg19: chrX-154005112;