rs179363896

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001099857.5(IKBKG):c.337G>A(p.Asp113Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 0 hom., 4 hem., cov: 15)

Exomes 𝑓: 0.0086 ( 0 hom. 20 hem. )

Failed GnomAD Quality Control

Consequence

IKBKG
NM_001099857.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:5O:1

Conservation

PhyloP100: 1.69

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006111324).

BP6

Variant X-154556314-G-A is Benign according to our data. Variant chrX-154556314-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 68235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154556314-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00861 (2992/347339) while in subpopulation NFE AF= 0.00979 (2067/211199). AF 95% confidence interval is 0.00944. There are 0 homozygotes in gnomad4_exome. There are 20 alleles in male gnomad4_exome subpopulation. Median coverage is 4. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKG	NM_001099857.5 link	c.337G>A	p.Asp113Asn	missense_variant	Exon 3 of 10	ENST00000594239.6	NP_001093327.1	Q9Y6K9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKG	ENST00000594239.6 link	c.337G>A	p.Asp113Asn	missense_variant	Exon 3 of 10	1	NM_001099857.5	ENSP00000471166.1		Q9Y6K9-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

624

AN:

87553

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

15687

FAILED QC

Gnomad AFR

AF:

0.00185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00290

Gnomad ASJ

AF:

0.00688

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00524

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0101

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00707

GnomAD3 exomes

AF:

0.00957

AC:

292

AN:

30507

Hom.:

AF XY:

0.0108

AC XY:

AN XY:

7517

show subpopulations

Gnomad AFR exome

AF:

0.00309

Gnomad AMR exome

AF:

0.00440

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0184

Gnomad FIN exome

AF:

0.0326

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.00960

GnomAD4 exome

AF:

0.00861

AC:

2992

AN:

347339

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

119385

show subpopulations

Gnomad4 AFR exome

AF:

0.000863

Gnomad4 AMR exome

AF:

0.00275

Gnomad4 ASJ exome

AF:

0.00573

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00647

Gnomad4 FIN exome

AF:

0.0175

Gnomad4 NFE exome

AF:

0.00979

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00711

AC:

623

AN:

87572

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

AN XY:

15730

show subpopulations

Gnomad4 AFR

AF:

0.00184

Gnomad4 AMR

AF:

0.00289

Gnomad4 ASJ

AF:

0.00688

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00528

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.0110

Gnomad4 OTH

AF:

0.00699

Alfa

AF:

0.00807

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Mar 10, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate no damaging effect (Fusco et al., 2004; Frans et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19903677, 26795245, 28679735, 18350553, 15229184, 22566850, 18179816, 28993958, 25068423, 20529958, 31965418) -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 25, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Immunodeficiency 33

Pathogenic:1

Aug 15, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ectodermal dysplasia and immunodeficiency 1

Benign:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Immunodeficiency 3 (MIM#3300636) and ectodermal dysplasia and immunodeficiency 1 (MIM#300291). (SB) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has previously been reported as likely benign and as a variant of uncertain significance (ClinVar). However, it has more recently been suggested to be non disease-causing due to population frequency (PMID: 33224153; 30422821). In addition, this variant was identified in a patient with recurrent bacterial and viral infections since his third month of life but the variant was also identified is the proband's 40 year old healthy cousin (PMID: 31965418) (I) 1004 - This variant has moderate functional evidence supporting normal protein function (PMID: 28993958). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;T;.;T;T;T;T;T;.;.;T;.

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.76

T;T;T;T;.;T;T;T;T;T;T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0061

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

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.2

.;.;.;.;L;.;.;.;.;L;L;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.3

N;N;.;N;.;N;.;.;.;.;.;.

REVEL

Benign

0.19

Sift

Benign

0.051

T;T;.;T;.;T;.;.;.;.;.;.

Sift4G

Benign

0.10

T;T;D;D;T;T;T;T;T;T;T;D

Polyphen

0.96, 0.17, 0.71

.;.;D;.;B;.;.;.;.;P;B;.

Vest4

0.27, 0.30, 0.31, 0.50, 0.66, 0.28, 0.32

MutPred

0.19

Loss of ubiquitination at K115 (P = 0.0468);Loss of ubiquitination at K115 (P = 0.0468);.;Loss of ubiquitination at K115 (P = 0.0468);Loss of ubiquitination at K115 (P = 0.0468);.;Loss of ubiquitination at K115 (P = 0.0468);Loss of ubiquitination at K115 (P = 0.0468);Loss of ubiquitination at K115 (P = 0.0468);Loss of ubiquitination at K115 (P = 0.0468);Loss of ubiquitination at K115 (P = 0.0468);.;

MVP

0.89

ClinPred

0.0079

GERP RS

4.4

Varity_R

0.063

gMVP

0.30

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