rs179363867

Variant names:

• chrX-154563577-G-A
• rs179363867
• NM_001099857.5:c.931G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV000698207: 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).".

• 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
• Publications: 36 publications found

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]

IKBKG Gene-Disease associations (from GenCC):

• ectodermal dysplasia and immunodeficiency 1

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• IKBKG-related immunodeficiency with or without ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• incontinentia pigmenti

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen, Orphanet
• ectodermal dysplasia and immune deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 33

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000698207: 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).
• 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 VariationId is 68239.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099857.5. 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
	IKBKG	NM_001099857.5	MANE Select	c.931G>A	p.Asp311Asn	missense	Exon 8 of 10	NP_001093327.1	Q9Y6K9-1
	IKBKG	NM_001099856.6		c.1135G>A	p.Asp379Asn	missense	Exon 8 of 10	NP_001093326.2	Q9Y6K9-2
	IKBKG	NM_001321396.3		c.931G>A	p.Asp311Asn	missense	Exon 8 of 10	NP_001308325.1	Q9Y6K9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKG	ENST00000594239.6	TSL:1 MANE Select	c.931G>A	p.Asp311Asn	missense	Exon 8 of 10	ENSP00000471166.1	Q9Y6K9-1
	IKBKG	ENST00000618670.4	TSL:1	c.1135G>A	p.Asp379Asn	missense	Exon 8 of 10	ENSP00000483825.1	Q9Y6K9-2
	IKBKG	ENST00000611071.4	TSL:1	c.931G>A	p.Asp311Asn	missense	Exon 8 of 10	ENSP00000479662.1	Q9Y6K9-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ectodermal dysplasia and immunodeficiency 1 (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.0
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.52		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

Other links and lift over

dbSNP: rs179363867; hg19: chrX-153791792;