rs148695964

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_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:4O:1

Conservation

PhyloP100: 5.17

Publications

15 publications found

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 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), ClinGen, Genomics England PanelApp, G2P, 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

IKBKG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027626723).

BP6

Variant X-154552171-G-A is Benign according to our data. Variant chrX-154552171-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 168 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKG	NM_001099857.5 link	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 link	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.:

Cov.:

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

GnomAD2 exomes

AF:

0.00110

AC:

185

AN:

167976

AF XY:

0.00105

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 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

African (AFR)

AF:

0.000116

AC:

AN:

25912

American (AMR)

AF:

0.00116

AC:

AN:

33697

Ashkenazi Jewish (ASJ)

AF:

0.00470

AC:

AN:

18730

East Asian (EAS)

AF:

0.00

AC:

AN:

29478

South Asian (SAS)

AF:

0.0000194

AC:

AN:

51536

European-Finnish (FIN)

AF:

0.000425

AC:

AN:

39973

Middle Eastern (MID)

AF:

0.000253

AC:

AN:

3953

European-Non Finnish (NFE)

AF:

0.00148

AC:

1226

AN:

828428

Other (OTH)

AF:

0.00173

AC:

AN:

45058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00150

AC:

168

AN:

111965

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

34129

show subpopulations

African (AFR)

AF:

0.000356

AC:

AN:

30868

American (AMR)

AF:

0.00293

AC:

AN:

10576

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3529

South Asian (SAS)

AF:

0.00

AC:

AN:

2700

European-Finnish (FIN)

AF:

0.000327

AC:

AN:

6114

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00186

AC:

AN:

53111

Other (OTH)

AF:

0.00264

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00170

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:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely 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

- -

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

- -

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 -

Incontinentia pigmenti syndrome;C1846008:Ectodermal dysplasia and immunodeficiency 1;C1970879:Immunodeficiency 33;C5676885:Autoinflammatory disease, X-linked

Benign:1

May 07, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

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

MutationAssessor

Uncertain

2.5

.;.;.;.;M;.;.;.;.;M;M;.

PhyloP100

5.2

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

PromoterAI

0.029

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over