rs179363895

chrX-154556344-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PS1_Moderate BP4

The NM_001099857.5(IKBKG):c.367C>T(p.Arg123Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., 0 hem., cov: 12)
  • Exomes 𝑓: 0.0 (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: 0.100

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 1 ACMG points.

• PS1: Transcript NM_001099857.5 (IKBKG) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.2924406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKG	NM_001099857.5	c.367C>T	p.Arg123Trp	missense_variant	3/10	ENST00000594239.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKG	ENST00000594239.6	c.367C>T	p.Arg123Trp	missense_variant	3/10	1	NM_001099857.5	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 77659 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 11057 FAILED QC

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00101

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 338386 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 117792

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000258 AC: 2 AN: 77659 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 11057

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00101

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.083	T;T;.;T;D;T;T;T;.;.;D;.
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.87	D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.1	D;D;.;D;.;D;.;.;.;.;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D;D;.;D;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.95, 0.88	.;.;D;.;P;.;.;.;.;P;P;.
Vest4		0.14, 0.13, 0.12, 0.079, 0.080, 0.11, 0.13
MutPred		0.36		Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);.;Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);.;Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);.;
MVP		0.96
ClinPred		0.65	D
GERP RS		1.4
Varity_R		0.11
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs179363895; hg19: chrX-153784559;