rs179363867

Positions:

• chrX-154563577-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Moderate PP5_Moderate

The NM_001099857.5(IKBKG):​c.931G>A​(p.Asp311Asn) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: IKBKG NM_001099857.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant X-154563577-G-A is Pathogenic according to our data. Variant chrX-154563577-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68239.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKG	NM_001099857.5	c.931G>A	p.Asp311Asn	missense_variant	8/10	ENST00000594239.6	NP_001093327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKG	ENST00000594239.6	c.931G>A	p.Asp311Asn	missense_variant	8/10	1	NM_001099857.5	ENSP00000471166	P3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 12, 2016

Variant summary: The IKBKG c.931G>A (p.Asp311Asn) variant involves the alteration of a conserved nucleotide and is located in the NF-kappa-B essential modulator NEMO, CC2-LZ domain of the protein. 3/4 in silico tools predict a damaging outcome for this variant. The frequency this variant in population control cohorts from ExAC or NHLBI ESP is not available due to lack of coverage of this chromosomal region. This variant has been reported in at least two EDA-ID patients in literature and was absent in the tested 200 control chromosomes (Doffinger_2001, Haverkamp_2014). Functional studies showed that the mutant D311N disrupts monoubiquitin, K63-linked, and linear polyubiquitin binding without affecting the protein folding or total amount of protein production (Hubean_2011). The variant was also shown to cause an impaired cytokine (IL-12) production. IKBKG can function as an intermediary in the NF-kappaB signal transduction through the recuitment of the IKK complex at the occupied cytokine receptors. The variant D311N impairs recognition of ubiquitnated proteins such as receptor interacting protein 1, RIP1 by IKBKG and thus the recruitment of the IKK complex to TNF-R1 (Fusco_2008). The residue p.D311 is highly conserved and another missense change at this residue p.D311G was found in a HED-IP patient and the variant was found to be functionally compromised (Hubean_2011), further supporting the pathogenicity of the variant of interest. Taken together, this variant is currently classified as likely pathogenic. -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;D;T;T;.;.;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.025	D;D;T;T;D;D;D
Polyphen		1.0	D;D;.;.;.;D;D
Vest4		0.89
MutPred		0.52		.;Gain of MoRF binding (P = 0.0279);.;.;.;.;Gain of MoRF binding (P = 0.0279);
MVP		0.98
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.68
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs179363867; hg19: chrX-153791792;