rs1127051

Variant names:

• chrX-154776309-C-T
• rs1127051
• NM_001363.5:c.1461C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154776309-C-T
• chrX-154776309-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001363.5(DKC1):​c.1461C>T​(p.Ala487Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,193,942 control chromosomes in the GnomAD database, including 1,815 homozygotes. There are 22,899 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (273 hom., 2194 hem., cov: 23)
  • Exomes 𝑓: 0.061 (1542 hom. 20705 hem.)
• Consequence: DKC1 NM_001363.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.809
• Publications: 8 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant X-154776309-C-T is Benign according to our data. Variant chrX-154776309-C-T is described in ClinVar as Benign. ClinVar VariationId is 128896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.809 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

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.1461C>T	p.Ala487Ala	synonymous	Exon 14 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.1446C>T	p.Ala482Ala	synonymous	Exon 14 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.*687C>T		3_prime_UTR	Exon 13 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.1461C>T	p.Ala487Ala	synonymous	Exon 14 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.2174C>T		non_coding_transcript_exon	Exon 13 of 14
	DKC1	ENST00000953351.1		c.1497C>T	p.Ala499Ala	synonymous	Exon 14 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes AF: 0.0722 AC: 8075 AN: 111859 Hom.: 273 Cov.: 23

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.0272

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.00443

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.0596

GnomAD2 exomes AF: 0.0522 AC: 7864 AN: 150590 AF XY: 0.0464

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.0450

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0512

GnomAD4 exome AF: 0.0610 AC: 66020 AN: 1082032 Hom.: 1542 Cov.: 31 AF XY: 0.0588 AC XY: 20705 AN XY: 352114

African (AFR) AF: 0.123 AC: 3201 AN: 26023

American (AMR) AF: 0.0341 AC: 1105 AN: 32391

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 546 AN: 19121

East Asian (EAS) AF: 0.0467 AC: 1372 AN: 29368

South Asian (SAS) AF: 0.00556 AC: 291 AN: 52314

European-Finnish (FIN) AF: 0.0463 AC: 1839 AN: 39678

Middle Eastern (MID) AF: 0.0127 AC: 52 AN: 4098

European-Non Finnish (NFE) AF: 0.0661 AC: 55058 AN: 833533

Other (OTH) AF: 0.0562 AC: 2556 AN: 45506

GnomAD4 genome AF: 0.0722 AC: 8084 AN: 111910 Hom.: 273 Cov.: 23 AF XY: 0.0643 AC XY: 2194 AN XY: 34140

African (AFR) AF: 0.120 AC: 3683 AN: 30725

American (AMR) AF: 0.0484 AC: 515 AN: 10642

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 72 AN: 2648

East Asian (EAS) AF: 0.0369 AC: 131 AN: 3547

South Asian (SAS) AF: 0.00444 AC: 12 AN: 2702

European-Finnish (FIN) AF: 0.0392 AC: 240 AN: 6117

Middle Eastern (MID) AF: 0.0323 AC: 7 AN: 217

European-Non Finnish (NFE) AF: 0.0628 AC: 3335 AN: 53115

Other (OTH) AF: 0.0588 AC: 89 AN: 1513

Alfa AF: 0.0687 Hom.: 2281

Bravo AF: 0.0768

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Dyskeratosis congenita (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.0
DANN	Benign	0.74
PhyloP100		-0.81
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1127051; hg19: chrX-154004584; COSMIC: COSV65729532; COSMIC: COSV65729532;