X-154558649-C-T

Variant names:

• chrX-154558649-C-T
• rs179363866
• NM_001099857.5:c.517C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5

The NM_001099857.5(IKBKG):​c.517C>T​(p.Arg173Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 0.0000067 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IKBKG NM_001099857.5 missense, splice_region
• Scores: Splicing: ADA: 0.004047
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13
• Publications: 5 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 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154558649-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11469.Status of the report is no_assertion_criteria_provided, 0 stars.

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.517C>T	p.Arg173Trp	missense splice_region	Exon 4 of 10	NP_001093327.1
	IKBKG	NM_001099856.6		c.721C>T	p.Arg241Trp	missense splice_region	Exon 4 of 10	NP_001093326.2
	IKBKG	NM_001321396.3		c.517C>T	p.Arg173Trp	missense splice_region	Exon 4 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.517C>T	p.Arg173Trp	missense splice_region	Exon 4 of 10	ENSP00000471166.1
	IKBKG	ENST00000618670.4	TSL:1	c.721C>T	p.Arg241Trp	missense splice_region	Exon 4 of 10	ENSP00000483825.1
	IKBKG	ENST00000611071.4	TSL:1	c.517C>T	p.Arg173Trp	missense splice_region	Exon 4 of 10	ENSP00000479662.1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000671 AC: 7 AN: 1042828 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 322166

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

African (AFR) AF: 0.00 AC: 0 AN: 24910

American (AMR) AF: 0.0000287 AC: 1 AN: 34788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18830

East Asian (EAS) AF: 0.00 AC: 0 AN: 29895

South Asian (SAS) AF: 0.0000201 AC: 1 AN: 49865

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2696

European-Non Finnish (NFE) AF: 0.00000501 AC: 4 AN: 797943

Other (OTH) AF: 0.0000228 AC: 1 AN: 43927

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000481138), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 18

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.31		Loss of methylation at R173 (P = 0.0095)
MVP		0.89
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.17
gMVP		0.72
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0040
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.080		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: rs179363866; hg19: chrX-153786864;