X-154558649-C-T

Position:

• chrX-154558649-C-T

Variant summary

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

The ENST00000594239.6(IKBKG):​c.517C>T​(p.Arg173Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R173G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 0.0000067 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IKBKG ENST00000594239.6 missense, splice_region
• Scores: Splicing: ADA: 0.004047
• Clinical Significance: Not reported in ClinVar
• 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 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 ENST00000594239.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154558650-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 377974.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKG	NM_001099857.5	c.517C>T	p.Arg173Trp	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>T	p.Arg173Trp	missense_variant, splice_region_variant	4/10	1	NM_001099857.5	ENSP00000471166	P3

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000671 AC: 7 AN: 1042828 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 322166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000201

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000501

Gnomad4 OTH exome AF: 0.0000228

GnomAD4 genome Cov.: 18

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;D;T;T;T;.;.;T;D
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;.;L;.;.;.;.;L;.;L
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.4	D;.;.;D;.;.;.;.;.;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;.;.;.;D;.;D
Vest4		0.31, 0.30, 0.30, 0.30, 0.33, 0.37
MutPred		0.31		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		0.89
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.17
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0040
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.080		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: rs179363866; hg19: chrX-153786864;