rs199422241

Variant names:

• chrX-154762824-C-G
• rs199422241
• ENST00000620277.4:n.83C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-154762824-C-G
• chrX-154762824-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000953351.1(DKC1):​c.-142C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 790,181 control chromosomes in the GnomAD database, including 1 homozygotes. There are 715 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 0.0022 (0 hom., 67 hem., cov: 25)
  • Exomes 𝑓: 0.0037 (1 hom. 648 hem.)
• Consequence: DKC1 ENST00000953351.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:9 O:1
• Conservation: PhyloP100: 0.868
• Publications: 5 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-154762824-C-G is Benign according to our data. Variant chrX-154762824-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38944.
• BS2: High AC in GnomAd4 at 254 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000953351.1. 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.-142C>G		upstream_gene	N/A	NP_001354.1	O60832-1
	DKC1	NM_001142463.3		c.-142C>G		upstream_gene	N/A	NP_001135935.1	A0A8Q3SIY6
	DKC1	NM_001288747.2		c.-142C>G		upstream_gene	N/A	NP_001275676.1	O60832-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKC1	ENST00000620277.4	TSL:1	n.83C>G		non_coding_transcript_exon	Exon 1 of 14
	DKC1	ENST00000953351.1		c.-142C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000623410.1
	DKC1	ENST00000939406.1		c.-142C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000609465.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 254 AN: 113679 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000638

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000915

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: 0.00434

Gnomad OTH AF: 0.000648

GnomAD4 exome AF: 0.00371 AC: 2510 AN: 676450 Hom.: 1 Cov.: 10 AF XY: 0.00359 AC XY: 648 AN XY: 180692

African (AFR) AF: 0.000604 AC: 10 AN: 16569

American (AMR) AF: 0.000446 AC: 11 AN: 24653

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14821

East Asian (EAS) AF: 0.00 AC: 0 AN: 24059

South Asian (SAS) AF: 0.000254 AC: 10 AN: 39418

European-Finnish (FIN) AF: 0.000398 AC: 13 AN: 32629

Middle Eastern (MID) AF: 0.000669 AC: 2 AN: 2990

European-Non Finnish (NFE) AF: 0.00486 AC: 2381 AN: 490002

Other (OTH) AF: 0.00265 AC: 83 AN: 31309

GnomAD4 genome AF: 0.00223 AC: 254 AN: 113731 Hom.: 0 Cov.: 25 AF XY: 0.00187 AC XY: 67 AN XY: 35881

African (AFR) AF: 0.000636 AC: 20 AN: 31438

American (AMR) AF: 0.0000914 AC: 1 AN: 10945

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2662

East Asian (EAS) AF: 0.00 AC: 0 AN: 3596

South Asian (SAS) AF: 0.00 AC: 0 AN: 2857

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6361

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00434 AC: 232 AN: 53405

Other (OTH) AF: 0.000639 AC: 1 AN: 1564

Alfa AF: 0.00108 Hom.: 8

Bravo AF: 0.00208

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	2	Dyskeratosis congenita, X-linked (6)
-	1	3	not provided (4)
-	1	2	Dyskeratosis congenita (3)
-	1	1	not specified (2)
-	-	1	DKC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.7
DANN	Benign	0.66
PhyloP100		0.87
PromoterAI		-0.089	Neutral
Mutation Taster		=300/0	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199422241;

hg19: chrX-153991099;