rs137853331

Positions:

• chrX-154563590-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP3 PP5_Moderate

The NM_001099857.5(IKBKG):​c.944A>C​(p.Glu315Ala) 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:2
• Conservation: PhyloP100: 8.35

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a mutagenesis_site Greatly impairs tandem ubiquitin binding. (size 0) in uniprot entity NEMO_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant X-154563590-A-C is Pathogenic according to our data. Variant chrX-154563590-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11467.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.944A>C	p.Glu315Ala	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.944A>C	p.Glu315Ala	missense_variant	8/10	1	NM_001099857.5	ENSP00000471166.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 33 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 10, 2006

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2023

Published functional studies demonstrate a damaging effect on protein function (PMID: 19185524); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26085218, 26240016, 19414794, 24682681, 18350553, 28679735, 15661019, 26230867, 22236433, 36569938, 25703555, 16818673, 25764117, 27744027, 24840983, 31123910, 35289316, 35159348, 18851874, 19185524) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;T;T;.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.;.;M
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;D
Vest4		0.92
MutPred		0.12		.;Gain of MoRF binding (P = 0.0205);.;.;.;.;Gain of MoRF binding (P = 0.0205);
MVP		1.0
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.61
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs137853331; hg19: chrX-153791805;