rs374771308

chrX-154767364-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS2

The NM_001363.5(DKC1):c.622G>A(p.Asp208Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000587 in 1,210,012 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000052 (0 hom. 21 hem.)
• Consequence: DKC1 NM_001363.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.55

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DKC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.39444476).
• BP6: Variant X-154767364-G-A is Benign according to our data. Variant chrX-154767364-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567290.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKC1	NM_001363.5	c.622G>A	p.Asp208Asn	missense_variant	7/15	ENST00000369550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKC1	ENST00000369550.10	c.622G>A	p.Asp208Asn	missense_variant	7/15	1	NM_001363.5	P2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 14 AN: 112011 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34205

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000757

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: 0.0000751

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.0000163 AC: 3 AN: 183518 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000519 AC: 57 AN: 1098001 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 21 AN XY: 363359

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000499

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000125 AC: 14 AN: 112011 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34205

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000757

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000751

Gnomad4 OTH AF: 0.00133

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.000363

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dyskeratosis congenita Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 2022	The c.622G>A (p.D208N) alteration is located in exon 7 (coding exon 7) of the DKC1 gene. This alteration results from a G to A substitution at nucleotide position 622, causing the aspartic acid (D) at amino acid position 208 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	26
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.84	.;P;.
Vest4		0.72
MVP		0.95
MPC		1.8
ClinPred		0.35	T
GERP RS		5.0
Varity_R		0.64
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs374771308; hg19: chrX-153995639; COSMIC: COSV65777221; COSMIC: COSV65777221;