rs782604431

Variant names:

• chrX-154552187-G-A
• rs782604431
• NM_001099857.5:c.185G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001099857.5(IKBKG):​c.185G>A​(p.Arg62Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,185,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 46 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00015 (0 hom. 43 hem.)
• Consequence: IKBKG NM_001099857.5 missense, splice_region
• Scores: Splicing: ADA: 0.6765
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 3.44
• Publications: 4 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), Genomics England PanelApp, G2P, ClinGen, 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3725457).
• BS2: High AC in GnomAd4 at 11 XL,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKG	NM_001099857.5	MANE Select	c.185G>A	p.Arg62Gln	missense splice_region	Exon 2 of 10	NP_001093327.1	Q9Y6K9-1
	IKBKG	NM_001099856.6		c.389G>A	p.Arg130Gln	missense splice_region	Exon 2 of 10	NP_001093326.2	Q9Y6K9-2
	IKBKG	NM_001321396.3		c.185G>A	p.Arg62Gln	missense splice_region	Exon 2 of 10	NP_001308325.1	Q9Y6K9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKG	ENST00000594239.6	TSL:1 MANE Select	c.185G>A	p.Arg62Gln	missense splice_region	Exon 2 of 10	ENSP00000471166.1	Q9Y6K9-1
	IKBKG	ENST00000618670.4	TSL:1	c.389G>A	p.Arg130Gln	missense splice_region	Exon 2 of 10	ENSP00000483825.1	Q9Y6K9-2
	IKBKG	ENST00000611071.4	TSL:1	c.185G>A	p.Arg62Gln	missense splice_region	Exon 2 of 10	ENSP00000479662.1	Q9Y6K9-1

Frequencies

GnomAD3 genomes AF: 0.0000981 AC: 11 AN: 112141 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000942

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: 0.000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 4 AN: 166227 AF XY: 0.0000376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000402

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000150 AC: 161 AN: 1073573 Hom.: 0 Cov.: 29 AF XY: 0.000125 AC XY: 43 AN XY: 343741

African (AFR) AF: 0.00 AC: 0 AN: 25884

American (AMR) AF: 0.0000296 AC: 1 AN: 33792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18717

East Asian (EAS) AF: 0.00 AC: 0 AN: 29325

South Asian (SAS) AF: 0.00 AC: 0 AN: 51242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39739

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3878

European-Non Finnish (NFE) AF: 0.000190 AC: 157 AN: 826095

Other (OTH) AF: 0.0000668 AC: 3 AN: 44901

GnomAD4 genome AF: 0.0000981 AC: 11 AN: 112141 Hom.: 0 Cov.: 23 AF XY: 0.0000875 AC XY: 3 AN XY: 34283

African (AFR) AF: 0.00 AC: 0 AN: 30851

American (AMR) AF: 0.0000942 AC: 1 AN: 10612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2729

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6151

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53165

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Ectodermal dysplasia and immunodeficiency 1 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.46
MutPred		0.34		Loss of MoRF binding (P = 0.0359)
MVP		0.99
ClinPred		0.69	D
GERP RS		5.6
PromoterAI		0.040	Neutral
Varity_R		0.52
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.68
dbscSNV1_RF	Pathogenic	0.77
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: rs782604431; hg19: chrX-153780402;