Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_001099857.5(IKBKG):c.1167dupC(p.Glu390ArgfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).
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]
Our verdict: Pathogenic. The variant received 12 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-G-GC is Pathogenic according to our data. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154564361-G-GC is described in CliVar as Pathogenic. Clinvar id is 372387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Department of Medical Genetics, College of Basic Medicine, Army Medical University
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research
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GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
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Immunodeficiency 33Pathogenic:1
May 10, 2023
Undiagnosed Diseases Network, NIH
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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not providedPathogenic:1
Dec 14, 2022
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Published functional studies demonstrate a damaging effect on protein function (Ohnishi et al., 2017; Kawai et al., 2012); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost and replaced with 4 incorrect amino acids; truncated region removes a portion of the zinc finger domain (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22517901, 18350553, 11484156, 18347290, 30982207, 31713830, 32035679, 34061330, 11047757, 27577878, 18222329, 11179023, 28702714) -
Ectodermal dysplasia and immunodeficiency 1Pathogenic:1
Sep 01, 2001
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only
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Incontinentia pigmenti syndrome;C1846008:Ectodermal dysplasia and immunodeficiency 1;C1970879:Immunodeficiency 33Pathogenic:1