X-154542411-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.445

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 GnomAd at 22 XL gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000748 AC: 84 AN: 112328 Hom.: 1 Cov.: 24 AF XY: 0.000638 AC XY: 22 AN XY: 34496

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.: 1 AF XY: 0.00254 AC XY: 137 AN XY: 53881

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.: 3 Cov.: 30 AF XY: 0.00161 AC XY: 567 AN XY: 352855

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: 84 AN: 112380 Hom.: 1 Cov.: 24 AF XY: 0.000637 AC XY: 22 AN XY: 34558

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.: 3

Bravo AF: 0.000412

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000728 AC: 4

ExAC AF: 0.00207 AC: 249

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	2.0
Dann	Benign	0.75
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.035
MVP		0.13
ClinPred		0.0013	T
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

Other links and lift over

dbSNP: rs189237568; hg19: chrX-153770626; COSMIC: COSV63669442; COSMIC: COSV63669442;