rs782604431

Positions:

chrX-154552187-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_001099857.5(IKBKG):c.185G>A(p.Arg62Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,185,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 46 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.00015 ( 0 hom. 43 hem. )

Consequence

IKBKG
NM_001099857.5 missense, splice_region

Scores

Splicing: ADA: 0.6765

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 3.44

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 Likely_benign. Variant got -1 ACMG points.

PP5

Variant X-154552187-G-A is Pathogenic according to our data. Variant chrX-154552187-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430903.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.3725457). . Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAd4 at 3 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKG	NM_001099857.5 linkuse as main transcript	c.185G>A	p.Arg62Gln	missense_variant, splice_region_variant	2/10	ENST00000594239.6	NP_001093327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKG	ENST00000594239.6 linkuse as main transcript	c.185G>A	p.Arg62Gln	missense_variant, splice_region_variant	2/10	1	NM_001099857.5	ENSP00000471166	P3	Q9Y6K9-1

Frequencies

GnomAD3 genomes

AF:

0.0000981

AC:

AN:

112141

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34283

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000942

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

166227

Hom.:

AF XY:

0.0000376

AC XY:

AN XY:

53225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000402

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

161

AN:

1073573

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

343741

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000296

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000190

Gnomad4 OTH exome

AF:

0.0000668

GnomAD4 genome

AF:

0.0000981

AC:

AN:

112141

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34283

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000942

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Immunology, University Hospital Southampton NHSFT	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 11, 2024

Variant summary: IKBKG c.185G>A (p.Arg62Gln) results in a conservative amino acid change located in the NF-kappa-B essential modulator NEMO, N-terminal domain (IPR021063) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 166227 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.185G>A has been reported in the literature in a hemizygous individual affected with primary immunodeficiency (Rae_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29077208). ClinVar contains an entry for this variant (Variation ID: 430903). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2021

Unlikely to be causative of incontinentia pigmenti (XLD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

IKBKG: PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

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

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.37

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

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

0.64

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

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

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

REVEL

Uncertain

0.52

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.053

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

Polyphen

1.0, 1.0

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

Vest4

0.46, 0.22, 0.24, 0.26, 0.24, 0.51, 0.23

MutPred

0.34

Loss of MoRF binding (P = 0.0359);Loss of MoRF binding (P = 0.0359);.;Loss of MoRF binding (P = 0.0359);Loss of MoRF binding (P = 0.0359);.;Loss of MoRF binding (P = 0.0359);Loss of MoRF binding (P = 0.0359);Loss of MoRF binding (P = 0.0359);Loss of MoRF binding (P = 0.0359);Loss of MoRF binding (P = 0.0359);.;

MVP

0.99

ClinPred

0.69

GERP RS

5.6

Varity_R

0.52

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.68

dbscSNV1_RF

Pathogenic

0.77

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