rs179363866

Positions:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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. R173Q) has been classified as Likely pathogenic.

• 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 chrnull-null-null-null is described in UniProt as null.
• 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 id is 11469.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKG	NM_001099857.5	c.517C>G	p.Arg173Gly	missense_variant, splice_region_variant	4/10	ENST00000594239.6	NP_001093327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKG	ENST00000594239.6	c.517C>G	p.Arg173Gly	missense_variant, splice_region_variant	4/10	1	NM_001099857.5	ENSP00000471166	P3

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

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;.;D;T;T;T;.;.;T;D
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;.;D;D;D;D;T;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.8	.;.;L;.;.;.;.;L;.;L
MutationTaster	Benign	0.63	A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.1	D;.;.;D;.;.;.;.;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D;.;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.015	D;T;T;D;D;D;T;D;D;T
Polyphen		0.91, 0.80, 0.65	.;P;P;.;.;.;.;P;.;P
Vest4		0.60, 0.63, 0.48, 0.59, 0.73, 0.39, 0.62
MutPred		0.22		Loss of methylation at R173 (P = 0.0095);.;Loss of methylation at R173 (P = 0.0095);.;Loss of methylation at R173 (P = 0.0095);.;.;Loss of methylation at R173 (P = 0.0095);.;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

Publications

LitVar

Other links and lift over

dbSNP: rs179363866; hg19: chrX-153786864;