rs179363895

Variant names:

• chrX-154556344-C-T
• rs179363895
• NM_001099857.5:c.367C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001099857.5(IKBKG):​c.367C>T​(p.Arg123Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., 0 hem., cov: 12)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IKBKG NM_001099857.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.100
• Publications: 6 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2924406).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099857.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKG	NM_001099857.5	MANE Select	c.367C>T	p.Arg123Trp	missense	Exon 3 of 10	NP_001093327.1
	IKBKG	NM_001099856.6		c.571C>T	p.Arg191Trp	missense	Exon 3 of 10	NP_001093326.2
	IKBKG	NM_001321396.3		c.367C>T	p.Arg123Trp	missense	Exon 3 of 10	NP_001308325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKG	ENST00000594239.6	TSL:1 MANE Select	c.367C>T	p.Arg123Trp	missense	Exon 3 of 10	ENSP00000471166.1
	IKBKG	ENST00000618670.4	TSL:1	c.571C>T	p.Arg191Trp	missense	Exon 3 of 10	ENSP00000483825.1
	IKBKG	ENST00000611071.4	TSL:1	c.367C>T	p.Arg123Trp	missense	Exon 3 of 10	ENSP00000479662.1

Frequencies

GnomAD3 genomes AF: 0.0000258 AC: 2 AN: 77659 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00101

GnomAD2 exomes AF: 0.00 AC: 0 AN: 28948 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 338386 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 117792

African (AFR) AF: 0.00 AC: 0 AN: 10037

American (AMR) AF: 0.00 AC: 0 AN: 16285

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10264

East Asian (EAS) AF: 0.00 AC: 0 AN: 23577

South Asian (SAS) AF: 0.00 AC: 0 AN: 27606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22643

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1417

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 206325

Other (OTH) AF: 0.00 AC: 0 AN: 20232

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000258 AC: 2 AN: 77659 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 11057

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000488 AC: 1 AN: 20508

American (AMR) AF: 0.00 AC: 0 AN: 7138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1964

East Asian (EAS) AF: 0.00 AC: 0 AN: 2473

South Asian (SAS) AF: 0.00 AC: 0 AN: 1124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3169

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 190

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39628

Other (OTH) AF: 0.00101 AC: 1 AN: 989

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.34	N
PhyloP100		0.10
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.14
MutPred		0.36		Loss of MoRF binding (P = 0.0477)
MVP		0.96
ClinPred		0.65	D
GERP RS		1.4
Varity_R		0.11
gMVP		0.45

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: rs179363895; hg19: chrX-153784559;