rs782178147

Positions:

• chrX-154564361-GC-G
• chrX-154564361-GC-GCC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_001099857.5(IKBKG):​c.1167del​(p.Glu390ArgfsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: IKBKG NM_001099857.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0810

Genes affected

IKBKG (HGNC:5961): (inhibitor of nuclear factor kappa B kinase regulatory subunit gamma) This gene encodes the regulatory subunit of the inhibitor of kappaB kinase (IKK) complex, which activates NF-kappaB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways. Mutations in this gene result in incontinentia pigmenti, hypohidrotic ectodermal dysplasia, and several other types of immunodeficiencies. A pseudogene highly similar to this locus is located in an adjacent region of the X chromosome. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PP5: Variant X-154564361-GC-G is Pathogenic according to our data. Variant chrX-154564361-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1220510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154564361-GC-G is described in Lovd as [Pathogenic]. Variant chrX-154564361-GC-G is described in Lovd as [Pathogenic]. Variant chrX-154564361-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKG	NM_001099857.5	c.1167del	p.Glu390ArgfsTer61	frameshift_variant	10/10	ENST00000594239.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKG	ENST00000594239.6	c.1167del	p.Glu390ArgfsTer61	frameshift_variant	10/10	1	NM_001099857.5	P3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2024

Published functional studies demonstrate that the c.1167delC variant completely abolishes IKBKG activity (PMID: 11179023); Frameshift variant predicted to result in protein truncation, as the last 30 amino acids are replaced with 60 different amino acids, and other loss-of-function variants have been reported downstream (HGMD; PMID: 28702714, 22517901, 11179023); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24339369, 28702714, 22517901, 11179023, 22121116) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782178147; hg19: chrX-153792576;