rs179363866

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-154558649-C-G
• chrX-154558649-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_001099857.5(IKBKG):​c.517C>G​(p.Arg173Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). 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 missense, splice_region
• Scores: Splicing: ADA: 0.01393
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154558650-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 377974.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• PP5: Variant X-154558649-C-G is Pathogenic according to our data. 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>G	p.Arg173Gly	missense splice_region	Exon 4 of 10	NP_001093327.1
	IKBKG	NM_001099856.6		c.721C>G	p.Arg241Gly	missense splice_region	Exon 4 of 10	NP_001093326.2
	IKBKG	NM_001321396.3		c.517C>G	p.Arg173Gly	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>G	p.Arg173Gly	missense splice_region	Exon 4 of 10	ENSP00000471166.1
	IKBKG	ENST00000618670.4	TSL:1	c.721C>G	p.Arg241Gly	missense splice_region	Exon 4 of 10	ENSP00000483825.1
	IKBKG	ENST00000611071.4	TSL:1	c.517C>G	p.Arg173Gly	missense splice_region	Exon 4 of 10	ENSP00000479662.1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 18

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency 33 Pathogenic:1

Jan 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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	Benign	0.24
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.015	D
Polyphen		0.91	P
Vest4		0.60
MutPred		0.22		Loss of methylation at R173 (P = 0.0095)
MVP		1.0
ClinPred		0.94	D
GERP RS		3.0
Varity_R		0.26
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: -3

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

Other links and lift over

dbSNP: rs179363866; hg19: chrX-153786864;