rs137853322

Variant names:

• chrX-154564420-A-G
• rs137853322
• NM_001099857.5:c.1219A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_001099857.5(IKBKG):​c.1219A>G​(p.Met407Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: IKBKG NM_001099857.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 8.26
• Publications: 7 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant X-154564420-A-G is Pathogenic according to our data. Variant chrX-154564420-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11449.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1876359). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKG	NM_001099857.5	c.1219A>G	p.Met407Val	missense_variant	Exon 10 of 10	ENST00000594239.6	NP_001093327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKG	ENST00000594239.6	c.1219A>G	p.Met407Val	missense_variant	Exon 10 of 10	1	NM_001099857.5	ENSP00000471166.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.000686 AC: 43 AN: 62721 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000216

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00110

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.000505

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000759 Hom.: 0

ExAC AF: 0.000165 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Jul 21, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a 50% decrease in NF-kB signaling compared to wild-type (Cordier et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10839543, 11590134, 28679735, 19033441, 19404319, 27744027) -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IKBKG: PS4:Moderate, PS3:Supporting -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Incontinentia pigmenti syndrome Pathogenic:1

May 25, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	.;T;T;T;.;.;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.4	.;M;.;.;.;.;M
PhyloP100		8.3
PrimateAI	Uncertain	0.63	T
Sift4G	Uncertain	0.022	D;D;T;T;D;D;D
Polyphen		0.091	B;B;.;.;.;B;B
Vest4		0.50
MutPred		0.27		.;Loss of disorder (P = 0.1059);.;.;.;.;Loss of disorder (P = 0.1059);
MVP		0.98
ClinPred		0.066	T
GERP RS		4.1
Varity_R		0.36
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853322; hg19: chrX-153792635;