X-154762970-C-G

Variant names:

• chrX-154762970-C-G
• rs121912303
• NM_001363.5:c.5C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001363.5(DKC1):​c.5C>G​(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000936 in 1,068,811 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• 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

ENSG00000307948 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154762970-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38951.

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.5C>G	p.Ala2Gly	missense	Exon 1 of 15	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.5C>G	p.Ala2Gly	missense	Exon 1 of 15	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.5C>G	p.Ala2Gly	missense	Exon 1 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.5C>G	p.Ala2Gly	missense	Exon 1 of 15	ENSP00000358563.5	O60832-1
	DKC1	ENST00000620277.4	TSL:1	n.229C>G		non_coding_transcript_exon	Exon 1 of 14
	DKC1	ENST00000953351.1		c.5C>G	p.Ala2Gly	missense	Exon 1 of 15	ENSP00000623410.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 9.36e-7 AC: 1 AN: 1068811 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 347707

African (AFR) AF: 0.00 AC: 0 AN: 25728

American (AMR) AF: 0.00 AC: 0 AN: 30776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18805

East Asian (EAS) AF: 0.00 AC: 0 AN: 28574

South Asian (SAS) AF: 0.00 AC: 0 AN: 50839

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38163

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 826919

Other (OTH) AF: 0.00 AC: 0 AN: 44908

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.39
MutPred		0.45		Gain of relative solvent accessibility (P = 0.0024)
MVP		0.93
MPC		1.4
ClinPred		0.86	D
GERP RS		3.9
PromoterAI		-0.62	Under-expression
Varity_R		0.44
gMVP		0.65
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs121912303; hg19: chrX-153991245;