Genetic Variant IKBKG:p.Arg50Cys (chrX-154542411-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001099856.6(IKBKG):c.148C>T(p.Arg50Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,197,439 control chromosomes in the GnomAD database, including 4 homozygotes. There are 589 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., 22 hem., cov: 24)

Exomes 𝑓: 0.0012 ( 3 hom. 567 hem. )

Consequence

IKBKG
NM_001099856.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.445

Publications

6 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 links:

G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

G6PD Gene-Disease associations (from GenCC):

anemia, nonspherocytic hemolytic, due to G6PD deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
G6PD deficiency
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
class I glucose-6-phosphate dehydrogenase deficiency
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

G6PD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003347844).

BP6

Variant X-154542411-C-T is Benign according to our data. Variant chrX-154542411-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1699101.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000747 (84/112380) while in subpopulation SAS AF = 0.00993 (27/2718). AF 95% confidence interval is 0.00701. There are 1 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 84 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099856.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
G6PD	NM_001360016.2	MANE Select	c.120+3625G>A		intron	N/A	NP_001346945.1	A0A384NL00
IKBKG	NM_001099856.6		c.148C>T	p.Arg50Cys	missense	Exon 1 of 10	NP_001093326.2	Q9Y6K9-2
G6PD	NM_000402.4		c.210+3625G>A		intron	N/A	NP_000393.4	P11413-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IKBKG	ENST00000618670.4	TSL:1	c.148C>T	p.Arg50Cys	missense	Exon 1 of 10	ENSP00000483825.1	Q9Y6K9-2
G6PD	ENST00000393562.10	TSL:1 MANE Select	c.120+3625G>A		intron	N/A	ENSP00000377192.3	P11413-1
IKBKG	ENST00000612051.1	TSL:1	n.124+24C>T		intron	N/A	ENSP00000480431.1	A0A087WWQ9

Frequencies

GnomAD3 genomes

AF:

0.000748

AC:

AN:

112328

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000648

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00990

Gnomad FIN

AF:

0.000161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00149

AC:

245

AN:

164727

AF XY:

0.00254

show subpopulations

Gnomad AFR exome

AF:

0.000177

Gnomad AMR exome

AF:

0.0000835

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000638

Gnomad NFE exome

AF:

0.000586

Gnomad OTH exome

AF:

0.000510

GnomAD4 exome

AF:

0.00121

AC:

1318

AN:

1085059

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

567

AN XY:

352855

show subpopulations

African (AFR)

AF:

0.000233

AC:

AN:

25716

American (AMR)

AF:

0.0000601

AC:

AN:

33262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19016

East Asian (EAS)

AF:

0.000103

AC:

AN:

29213

South Asian (SAS)

AF:

0.0133

AC:

685

AN:

51639

European-Finnish (FIN)

AF:

0.0000990

AC:

AN:

40417

Middle Eastern (MID)

AF:

0.00268

AC:

AN:

4099

European-Non Finnish (NFE)

AF:

0.000698

AC:

584

AN:

836103

Other (OTH)

AF:

0.000504

AC:

AN:

45594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000747

AC:

AN:

112380

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

AN XY:

34558

show subpopulations

African (AFR)

AF:

0.0000647

AC:

AN:

30924

American (AMR)

AF:

0.00

AC:

AN:

10640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00993

AC:

AN:

2718

European-Finnish (FIN)

AF:

0.000161

AC:

AN:

6203

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

53225

Other (OTH)

AF:

0.00

AC:

AN:

1546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000326

Hom.:

Bravo

AF:

0.000412

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000728

AC:

ExAC

AF:

0.00207

AC:

249

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ectodermal dysplasia and immunodeficiency 1 (1)

IKBKG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.90

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.0

(source)

DANN

Benign

0.75

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.59

PhyloP100

-0.45

PrimateAI

Benign

0.31

Polyphen

0.0

Vest4

0.035

MVP

0.13

ClinPred

0.0013

GERP RS

-3.5

PromoterAI

-0.088

Neutral

(source)

gMVP

0.075

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over