rs148695964

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:3O:1

Conservation

PhyloP100: 5.17

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKG	NM_001099857.5 linkuse as main transcript	c.169G>A	p.Glu57Lys	missense_variant	2/10	ENST00000594239.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKG	ENST00000594239.6 linkuse as main transcript	c.169G>A	p.Glu57Lys	missense_variant	2/10	1	NM_001099857.5	P3	Q9Y6K9-1

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

168

AN:

111910

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

34064

show subpopulations

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.:

AF XY:

0.00105

AC XY:

AN XY:

54512

show subpopulations

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.:

Cov.:

AF XY:

0.00131

AC XY:

453

AN XY:

346027

show subpopulations

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.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

34129

show subpopulations

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.:

Bravo

AF:

0.00142

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00178

AC:

ExAC

AF:

0.00113

AC:

137

ClinVar

Significance: Benign/Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -

Immunodeficiency 33

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 14, 2023

- -

Common variable immunodeficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

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

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2023

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

BayesDel_noAF

Pathogenic

0.51

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;D;.;D;D;D;T;T;.;.;D;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

D;D;D;D;.;D;D;D;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.64

MutationTaster

Benign

0.98

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.73

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over