rs148695964

Variant names:

• chrX-154552171-G-A
• rs148695964
• NM_001099857.5:c.169G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001099857.5(IKBKG):​c.169G>A​(p.Glu57Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,188,730 control chromosomes in the GnomAD database, including 1 homozygotes. There are 498 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 45 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (1 hom. 453 hem.)
• Consequence: IKBKG NM_001099857.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:3 O:1
• Conservation: PhyloP100: 5.17

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027626723).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0015 (168/111965) while in subpopulation AMR AF= 0.00293 (31/10576). AF 95% confidence interval is 0.00212. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKG	NM_001099857.5	c.169G>A	p.Glu57Lys	missense_variant	Exon 2 of 10	ENST00000594239.6	NP_001093327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKG	ENST00000594239.6	c.169G>A	p.Glu57Lys	missense_variant	Exon 2 of 10	1	NM_001099857.5	ENSP00000471166.1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 168 AN: 111910 Hom.: 0 Cov.: 23 AF XY: 0.00132 AC XY: 45 AN XY: 34064

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.0190

Gnomad AMR AF: 0.00293

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000327

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.00186

Gnomad OTH AF: 0.00268

GnomAD3 exomes AF: 0.00110 AC: 185 AN: 167976 Hom.: 0 AF XY: 0.00105 AC XY: 57 AN XY: 54512

Gnomad AFR exome AF: 0.000158

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.00500

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00135 AC: 1453 AN: 1076765 Hom.: 1 Cov.: 29 AF XY: 0.00131 AC XY: 453 AN XY: 346027

Gnomad4 AFR exome AF: 0.000116

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00470

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000194

Gnomad4 FIN exome AF: 0.000425

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00150 AC: 168 AN: 111965 Hom.: 0 Cov.: 23 AF XY: 0.00132 AC XY: 45 AN XY: 34129

Gnomad4 AFR AF: 0.000356

Gnomad4 AMR AF: 0.00293

Gnomad4 ASJ AF: 0.00264

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000327

Gnomad4 NFE AF: 0.00186

Gnomad4 OTH AF: 0.00264

Alfa AF: 0.00182 Hom.: 57

Bravo AF: 0.00142

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00178 AC: 12

ExAC AF: 0.00113 AC: 137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Oct 30, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunodeficiency 33 Pathogenic:1

Jul 18, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Common variable immunodeficiency Uncertain:1

-

Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP)- HUVH-VHIR, Vall d'Hebron University Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

We found the IKBKG c.169G>A / p.Glu57Lys variant in an adult female patient with common variable immunodeficiency (CVID). The variant has a very low frequency in the reference population databases (gnomad v3.1.2 MAF:0.001). The patient had skewed X chromosome inactivation, causing predominant expression of the mutated allele. Different studies reported functional alterations of the nuclear factor-κB (NF-κB) pathway: Gautheron et al showed that p.Glu57Lys variant is associated with a defect in TRAF6-dependent signaling pathways (i.e. IL-1 beta signaling) (PMID: 20529958). Frans et al showed a decrease of IL6 induction upon stimulation with IL-1 beta and TNF-alpha in SV40-transformed NEMO -/- fibroblasts transduced with p.Glu57Lys NEMO (PMID: 28993958). The IKBKG p.Glu57Lys variant has been reported in female patients with mild forms of incontinentia pigmenti (IP) and in a male patient with immunodeficiency (including hypogammaglobulinemia) but without ectodermal dysplasia (PMIDs: 15229184, 20529958, 28993958). The p.Glu57Lys variant has also been identified in healthy individuals (both males and females), consistent with its relatively high allele frequency. Therefore, we consider it a Variant of Uncertain Significance -

IKBKG-related disorder Benign:1

Sep 17, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D;D;.;D;D;D;T;T;.;.;D;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.5	.;.;.;.;M;.;.;.;.;M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;D;.;D;.;D;.;.;.;.;.;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.033	D;D;D;D;D;D;T;D;D;T;D;D
Polyphen		1.0, 1.0, 1.0	.;.;D;.;D;D;.;.;.;D;D;.
Vest4		0.69, 0.43, 0.45, 0.57, 0.52, 0.68
MVP		1.0
ClinPred		0.067	T
GERP RS		5.6
Varity_R		0.84
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs148695964; hg19: chrX-153780386; COSMIC: COSV54838027; COSMIC: COSV54838027;