rs179363868

chrX-154560412-G-AchrX-154560412-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM5

The NM_001099857.5(IKBKG):c.524G>A(p.Arg175Gln) variant causes a missense change. 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. R175P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000098 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.0000030 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IKBKG NM_001099857.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Interaction with TANK (size 107) in uniprot entity NEMO_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_001099857.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKG	NM_001099857.5	c.524G>A	p.Arg175Gln	missense_variant	5/10	ENST00000594239.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKG	ENST00000594239.6	c.524G>A	p.Arg175Gln	missense_variant	5/10	1	NM_001099857.5	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 101770 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 28546 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000301 AC: 3 AN: 997040 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 305558

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000379

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000982 AC: 1 AN: 101791 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 28579

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000430

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;T;T;T;T;.;T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	D;D;.;D;T;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.94	N;.;.;N;.;.;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.060	T;.;.;D;.;.;.;.;.
Sift4G	Benign	0.10	T;T;T;T;T;T;T;D;T
Polyphen		1.0, 1.0	.;D;D;.;.;.;.;.;D
Vest4		0.23, 0.22, 0.23, 0.21, 0.22
MutPred		0.17		Loss of MoRF binding (P = 0.0113);.;Loss of MoRF binding (P = 0.0113);.;Loss of MoRF binding (P = 0.0113);.;.;.;Loss of MoRF binding (P = 0.0113);
MVP		0.97
ClinPred		0.77	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153788627;