NM_001099857.5:c.1217A>T

Variant names:

• chrX-154564418-A-T
• rs137853327
• NM_001099857.5:c.1217A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Moderate PP5_Moderate

The NM_001099857.5(IKBKG):​c.1217A>T​(p.Asp406Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: IKBKG NM_001099857.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.09
• Publications: 9 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 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant X-154564418-A-T is Pathogenic according to our data. Variant chrX-154564418-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 11457.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKG	NM_001099857.5	c.1217A>T	p.Asp406Val	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.1217A>T	p.Asp406Val	missense_variant	Exon 10 of 10	1	NM_001099857.5	ENSP00000471166.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Incontinentia pigmenti syndrome Pathogenic:1

Dec 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

ECTODERMAL DYSPLASIA AND IMMUNODEFICIENCY 1, MALE-RESTRICTED Pathogenic:1

Dec 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ectodermal dysplasia and immunodeficiency 1 Pathogenic:1

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;D;T;T;.;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.;.;M
PhyloP100		8.1
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;D
Vest4		0.87
MutPred		0.60		.;Gain of catalytic residue at D406 (P = 0.0461);.;.;.;.;Gain of catalytic residue at D406 (P = 0.0461);
MVP		1.0
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.69
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137853327; hg19: chrX-153792633;