X-154776309-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001363.5(DKC1):​c.1461C>G​(p.Ala487Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,082,095 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A487A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: DKC1 NM_001363.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.809
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-0.809 with no splicing effect.

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

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082095 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352137

African (AFR) AF: 0.00 AC: 0 AN: 26028

American (AMR) AF: 0.00 AC: 0 AN: 32397

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19121

East Asian (EAS) AF: 0.00 AC: 0 AN: 29369

South Asian (SAS) AF: 0.00 AC: 0 AN: 52314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4098

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 833576

Other (OTH) AF: 0.00 AC: 0 AN: 45508

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.2
DANN	Benign	0.64
PhyloP100		-0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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;