dbSNP rs137853322: IKBKG:p.Met407Val (chrX-154564420-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_001099857.5(IKBKG):c.1219A>G(p.Met407Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 0)

Consequence

IKBKG
NM_001099857.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 8.26

Publications

7 publications found

Variant links:

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

IKBKG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant X-154564420-A-G is Pathogenic according to our data. Variant chrX-154564420-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11449.

BP4

Computational evidence support a benign effect (MetaRNN=0.1876359). . Strength limited to SUPPORTING due to the PP5.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IKBKG	NM_001099857.5	MANE Select	c.1219A>G	p.Met407Val	missense	Exon 10 of 10	NP_001093327.1	Q9Y6K9-1
IKBKG	NM_001099856.6		c.1423A>G	p.Met475Val	missense	Exon 10 of 10	NP_001093326.2	Q9Y6K9-2
IKBKG	NM_001321396.3		c.1219A>G	p.Met407Val	missense	Exon 10 of 10	NP_001308325.1	Q9Y6K9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IKBKG	ENST00000594239.6	TSL:1 MANE Select	c.1219A>G	p.Met407Val	missense	Exon 10 of 10	ENSP00000471166.1	Q9Y6K9-1
IKBKG	ENST00000618670.4	TSL:1	c.1423A>G	p.Met475Val	missense	Exon 10 of 10	ENSP00000483825.1	Q9Y6K9-2
IKBKG	ENST00000611071.4	TSL:1	c.1219A>G	p.Met407Val	missense	Exon 10 of 10	ENSP00000479662.1	Q9Y6K9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000686

AC:

AN:

62721

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000216

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00110

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.000505

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000759

Hom.:

ExAC

AF:

0.000165

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Incontinentia pigmenti syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.42

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.19

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.4

PhyloP100

8.3

PrimateAI

Uncertain

0.63

Sift4G

Uncertain

0.022

Polyphen

0.091

Vest4

0.50

MutPred

0.27

Loss of disorder (P = 0.1059)

MVP

0.98

ClinPred

0.066

GERP RS

4.1

Varity_R

0.36

gMVP

0.50

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over