chrX-154560412-G-C

Variant names:

• chrX-154560412-G-C
• rs179363868
• NM_001099857.5:c.524G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_001099857.5(IKBKG):​c.524G>C​(p.Arg175Pro) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R175W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000010 (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: 4.74
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001099857.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

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.524G>C	p.Arg175Pro	missense	Exon 5 of 10	NP_001093327.1
	IKBKG	NM_001099856.6		c.728G>C	p.Arg243Pro	missense	Exon 5 of 10	NP_001093326.2
	IKBKG	NM_001321396.3		c.524G>C	p.Arg175Pro	missense	Exon 5 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.524G>C	p.Arg175Pro	missense	Exon 5 of 10	ENSP00000471166.1
	IKBKG	ENST00000618670.4	TSL:1	c.728G>C	p.Arg243Pro	missense	Exon 5 of 10	ENSP00000483825.1
	IKBKG	ENST00000611071.4	TSL:1	c.524G>C	p.Arg175Pro	missense	Exon 5 of 10	ENSP00000479662.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000100 AC: 1 AN: 997048 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 305566

⚠️ 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: 18859

American (AMR) AF: 0.00 AC: 0 AN: 26944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17835

East Asian (EAS) AF: 0.00 AC: 0 AN: 26012

South Asian (SAS) AF: 0.00 AC: 0 AN: 46840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25089

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2655

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 790911

Other (OTH) AF: 0.00 AC: 0 AN: 41903

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 19

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.29		Loss of MoRF binding (P = 5e-04)
MVP		1.0
ClinPred		0.88	D
GERP RS		4.1
Varity_R		0.52
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs179363868; hg19: chrX-153788627;