rs179363869

chrX-154561696-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_Moderate PM1 PP3_Moderate

The NM_001099857.5(IKBKG):c.680T>C(p.Leu227Pro) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 0)
• Consequence: IKBKG NM_001099857.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.53

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.

• PS1: Transcript NM_001099857.5 (IKBKG) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a region_of_interest Interaction with TANK (size 107) in uniprot entity NEMO_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_001099857.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKG	NM_001099857.5	c.680T>C	p.Leu227Pro	missense_variant	6/10	ENST00000594239.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKG	ENST00000594239.6	c.680T>C	p.Leu227Pro	missense_variant	6/10	1	NM_001099857.5	P3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;D;T;T;.;.;T;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;D;.;D;D;D;T;T;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.4	D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;T;T;T;T;D;D;D;T
Polyphen		1.0	.;D;D;.;.;.;D;.;D
Vest4		0.88, 0.87, 0.86, 0.87, 0.86, 0.81, 0.87
MutPred		0.56		Gain of glycosylation at L227 (P = 0.0168);.;Gain of glycosylation at L227 (P = 0.0168);Gain of glycosylation at L227 (P = 0.0168);.;.;.;.;Gain of glycosylation at L227 (P = 0.0168);
MVP		1.0
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.88
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs179363869; hg19: chrX-153789911;