X-154558649-CGG-GGC

Variant names:

• chrX-154558649-CGG-GGC
• NM_001099857.5:c.517_518+1delCGGinsGGC
• IKBKG p.Arg173Gly

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001099857.5(IKBKG):​c.517_518+1delCGGinsGGC​(p.Arg173Gly) variant causes a splice donor, missense, splice region, intron change. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 18)
• Consequence: IKBKG NM_001099857.5 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23
• Publications: 0 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: Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKG	NM_001099857.5	MANE Select	c.517_518+1delCGGinsGGC	p.Arg173Gly	splice_donor missense splice_region intron	N/A	NP_001093327.1	Q9Y6K9-1
	IKBKG	NM_001099856.6		c.721_722+1delCGGinsGGC	p.Arg241Gly	splice_donor missense splice_region intron	N/A	NP_001093326.2	Q9Y6K9-2
	IKBKG	NM_001321396.3		c.517_518+1delCGGinsGGC	p.Arg173Gly	splice_donor missense splice_region intron	N/A	NP_001308325.1	Q9Y6K9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKG	ENST00000594239.6	TSL:1 MANE Select	c.517_518+1delCGGinsGGC	p.Arg173Gly	splice_donor missense splice_region intron	N/A	ENSP00000471166.1	Q9Y6K9-1
	IKBKG	ENST00000618670.4	TSL:1	c.721_722+1delCGGinsGGC	p.Arg241Gly	splice_donor missense splice_region intron	N/A	ENSP00000483825.1	Q9Y6K9-2
	IKBKG	ENST00000611071.4	TSL:1	c.517_518+1delCGGinsGGC	p.Arg173Gly	splice_donor missense splice_region intron	N/A	ENSP00000479662.1	Q9Y6K9-1

Frequencies

GnomAD3 genomes Cov.: 18

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-153786864;