chrX-154542411-C-T

Position:

chrX-154542411-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000618670.4(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. 9/13 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
ENST00000618670.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.445

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1699101.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154542411-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 22 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2 linkuse as main transcript	c.120+3625G>A		intron_variant		ENST00000393562.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.120+3625G>A		intron_variant		1	NM_001360016.2	P4	P11413-1

Frequencies

GnomAD3 genomes

AF:

0.000748

AC:

AN:

112328

Hom.:

Cov.:

AF XY:

0.000638

AC XY:

AN XY:

34496

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

GnomAD3 exomes

AF:

0.00149

AC:

245

AN:

164727

Hom.:

AF XY:

0.00254

AC XY:

137

AN XY:

53881

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 SAS exome

AF:

0.0119

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

Gnomad4 AFR exome

AF:

0.000233

Gnomad4 AMR exome

AF:

0.0000601

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000103

Gnomad4 SAS exome

AF:

0.0133

Gnomad4 FIN exome

AF:

0.0000990

Gnomad4 NFE exome

AF:

0.000698

Gnomad4 OTH exome

AF:

0.000504

GnomAD4 genome

AF:

0.000747

AC:

AN:

112380

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

AN XY:

34558

show subpopulations

Gnomad4 AFR

AF:

0.0000647

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00993

Gnomad4 FIN

AF:

0.000161

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000602

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

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of ectodermal dysplasia and immunodeficiency 1 (MIM#300291), X-linked recessive immunodeficiency 33 (MIM#300636), and incontinentia pigmenti (MIM#308300). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

IKBKG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.90

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.0

DANN

Benign

0.75

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.59

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.31

Polyphen

0.0

Vest4

0.035

MVP

0.13

ClinPred

0.0013

GERP RS

-3.5

gMVP

0.075

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over