rs179363896

Variant names:

• chrX-154556314-G-A
• rs179363896
• NM_001099857.5:c.337G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001099857.5(IKBKG):​c.337G>A​(p.Asp113Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (0 hom., 4 hem., cov: 15)
  • Exomes 𝑓: 0.0086 (0 hom. 20 hem.)
  • Failed GnomAD Quality Control
• Consequence: IKBKG NM_001099857.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5 O:1
• Conservation: PhyloP100: 1.69
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006111324).
• BP6: Variant X-154556314-G-A is Benign according to our data. Variant chrX-154556314-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.337G>A	p.Asp113Asn	missense	Exon 3 of 10	NP_001093327.1
	IKBKG	NM_001099856.6		c.541G>A	p.Asp181Asn	missense	Exon 3 of 10	NP_001093326.2
	IKBKG	NM_001321396.3		c.337G>A	p.Asp113Asn	missense	Exon 3 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.337G>A	p.Asp113Asn	missense	Exon 3 of 10	ENSP00000471166.1
	IKBKG	ENST00000618670.4	TSL:1	c.541G>A	p.Asp181Asn	missense	Exon 3 of 10	ENSP00000483825.1
	IKBKG	ENST00000611071.4	TSL:1	c.337G>A	p.Asp113Asn	missense	Exon 3 of 10	ENSP00000479662.1

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 624 AN: 87553 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00290

Gnomad ASJ AF: 0.00688

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00524

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00707

GnomAD2 exomes AF: 0.00957 AC: 292 AN: 30507 AF XY: 0.0108

Gnomad AFR exome AF: 0.00309

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00960

GnomAD4 exome AF: 0.00861 AC: 2992 AN: 347339 Hom.: 0 Cov.: 4 AF XY: 0.000168 AC XY: 20 AN XY: 119385

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000863 AC: 9 AN: 10425

American (AMR) AF: 0.00275 AC: 51 AN: 18551

Ashkenazi Jewish (ASJ) AF: 0.00573 AC: 61 AN: 10646

East Asian (EAS) AF: 0.00 AC: 0 AN: 23690

South Asian (SAS) AF: 0.00647 AC: 180 AN: 27809

European-Finnish (FIN) AF: 0.0175 AC: 404 AN: 23030

Middle Eastern (MID) AF: 0.00684 AC: 10 AN: 1462

European-Non Finnish (NFE) AF: 0.00979 AC: 2067 AN: 211199

Other (OTH) AF: 0.0102 AC: 210 AN: 20527

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00711 AC: 623 AN: 87572 Hom.: 0 Cov.: 15 AF XY: 0.000254 AC XY: 4 AN XY: 15730

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00184 AC: 44 AN: 23870

American (AMR) AF: 0.00289 AC: 24 AN: 8296

Ashkenazi Jewish (ASJ) AF: 0.00688 AC: 15 AN: 2181

East Asian (EAS) AF: 0.00 AC: 0 AN: 2708

South Asian (SAS) AF: 0.00528 AC: 7 AN: 1327

European-Finnish (FIN) AF: 0.0118 AC: 46 AN: 3899

Middle Eastern (MID) AF: 0.00568 AC: 1 AN: 176

European-Non Finnish (NFE) AF: 0.0110 AC: 478 AN: 43439

Other (OTH) AF: 0.00699 AC: 8 AN: 1145

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00807 Hom.: 42

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	1	Ectodermal dysplasia and immunodeficiency 1 (1)
1	-	-	Immunodeficiency 33 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.0061	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.19
Sift	Benign	0.051	T
Sift4G	Benign	0.10	T
Polyphen		0.96	D
Vest4		0.27
MutPred		0.19		Loss of ubiquitination at K115 (P = 0.0468)
MVP		0.89
ClinPred		0.0079	T
GERP RS		4.4
Varity_R		0.063
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs179363896; hg19: chrX-153784529;