rs202220072

Variant names:

• chrX-154542282-G-A
• rs202220072
• ENST00000618670.4:c.19G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001321396.3(IKBKG):​c.-121G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,150,982 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 hemizygotes in GnomAD. 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: 𝑓 0.000098 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00014 (0 hom. 46 hem.)
• Consequence: IKBKG NM_001321396.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.452
• Publications: 2 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]

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07393476).
• BP6: Variant X-154542282-G-A is Benign according to our data. Variant chrX-154542282-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521562.
• BS2: High AC in GnomAd4 at 11 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321396.3. 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
	G6PD	NM_001360016.2	MANE Select	c.120+3754C>T		intron	N/A	NP_001346945.1	A0A384NL00
	IKBKG	NM_001321396.3		c.-121G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001308325.1	Q9Y6K9-1
	IKBKG	NM_001099856.6		c.19G>A	p.Val7Met	missense	Exon 1 of 10	NP_001093326.2	Q9Y6K9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKG	ENST00000618670.4	TSL:1	c.19G>A	p.Val7Met	missense	Exon 1 of 10	ENSP00000483825.1	Q9Y6K9-2
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.120+3754C>T		intron	N/A	ENSP00000377192.3	P11413-1
	IKBKG	ENST00000612051.1	TSL:1	n.19G>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000480431.1	A0A087WWQ9

Frequencies

GnomAD3 genomes AF: 0.0000981 AC: 11 AN: 112135 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

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: 0.000169

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000105 AC: 12 AN: 113793 AF XY: 0.0000826

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 147 AN: 1038847 Hom.: 0 Cov.: 27 AF XY: 0.000140 AC XY: 46 AN XY: 328989

African (AFR) AF: 0.00 AC: 0 AN: 24681

American (AMR) AF: 0.000108 AC: 3 AN: 27760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18487

East Asian (EAS) AF: 0.00 AC: 0 AN: 27084

South Asian (SAS) AF: 0.00 AC: 0 AN: 49087

European-Finnish (FIN) AF: 0.0000263 AC: 1 AN: 38005

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4031

European-Non Finnish (NFE) AF: 0.000174 AC: 140 AN: 805731

Other (OTH) AF: 0.0000682 AC: 3 AN: 43981

GnomAD4 genome AF: 0.0000981 AC: 11 AN: 112135 Hom.: 0 Cov.: 23 AF XY: 0.0000874 AC XY: 3 AN XY: 34313

African (AFR) AF: 0.0000324 AC: 1 AN: 30853

American (AMR) AF: 0.0000940 AC: 1 AN: 10643

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2717

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000169 AC: 9 AN: 53105

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.000171 Hom.: 9

Bravo AF: 0.000125

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000388 AC: 1

ESP6500EA AF: 0.000185 AC: 1

ExAC AF: 0.000239 AC: 25

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	0.25
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.5
DANN	Benign	0.69
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.33	T
PhyloP100		0.45
PrimateAI	Benign	0.33	T
Polyphen		0.089	B
Vest4		0.25
MVP		0.54
ClinPred		0.0091	T
GERP RS		-0.18
PromoterAI		0.0063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.050
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs202220072; hg19: chrX-153770497;