rs782159247

Variant names:

• chrX-154767035-A-C
• rs782159247
• NM_001363.5:c.487A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-154767035-A-C
• chrX-154767035-A-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001363.5(DKC1):​c.487A>C​(p.Ile163Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000401 in 1,097,892 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I163V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000040 (0 hom. 12 hem.)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.58
• 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: ClinGen, Labcorp Genetics (formerly Invitae), 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18955725).
• BS2: High AC in GnomAdExome4 at 44 XL,AD gene.

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.487A>C	p.Ile163Leu	missense	Exon 6 of 15	NP_001354.1
	DKC1	NM_001142463.3		c.487A>C	p.Ile163Leu	missense	Exon 6 of 15	NP_001135935.1
	DKC1	NM_001288747.2		c.487A>C	p.Ile163Leu	missense	Exon 6 of 14	NP_001275676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	ENST00000369550.10	TSL:1 MANE Select	c.487A>C	p.Ile163Leu	missense	Exon 6 of 15	ENSP00000358563.5
	DKC1	ENST00000620277.4	TSL:1	n.711A>C		non_coding_transcript_exon	Exon 6 of 14
	DKC1	ENST00000953351.1		c.487A>C	p.Ile163Leu	missense	Exon 6 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183519 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000401 AC: 44 AN: 1097892 Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 12 AN XY: 363250

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000523 AC: 44 AN: 841820

Other (OTH) AF: 0.00 AC: 0 AN: 46086

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.070	N
PhyloP100		4.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.065
Sift	Benign	0.41	T
Sift4G	Benign	0.34	T
Polyphen		0.0040	B
Vest4		0.31
MutPred		0.27		Gain of disorder (P = 0.1255)
MVP		0.49
MPC		1.4
ClinPred		0.39	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.91
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs782159247; hg19: chrX-153995310;