rs2472393

Variant names:

• chrX-154543081-T-C
• rs2472393
• NM_001360016.2:c.120+2955A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001360016.2(G6PD):​c.120+2955A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 111,337 control chromosomes in the GnomAD database, including 20,026 homozygotes. There are 21,919 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.65 (20026 hom., 21919 hem., cov: 23)
• Consequence: G6PD NM_001360016.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40
• Publications: 12 publications found

Genes affected

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]

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), ClinGen, Genomics England PanelApp, G2P, 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-154543081-T-C is Benign according to our data. Variant chrX-154543081-T-C is described in ClinVar as Benign. ClinVar VariationId is 1722713.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.120+2955A>G		intron_variant	Intron 2 of 12	ENST00000393562.10	NP_001346945.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.120+2955A>G		intron_variant	Intron 2 of 12	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes AF: 0.646 AC: 71934 AN: 111286 Hom.: 20029 Cov.: 23

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.923

Gnomad MID AF: 0.681

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.656

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.646 AC: 71940 AN: 111337 Hom.: 20026 Cov.: 23 AF XY: 0.654 AC XY: 21919 AN XY: 33529

African (AFR) AF: 0.153 AC: 4705 AN: 30653

American (AMR) AF: 0.732 AC: 7695 AN: 10510

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2038 AN: 2649

East Asian (EAS) AF: 0.871 AC: 3052 AN: 3506

South Asian (SAS) AF: 0.540 AC: 1440 AN: 2668

European-Finnish (FIN) AF: 0.923 AC: 5525 AN: 5983

Middle Eastern (MID) AF: 0.693 AC: 151 AN: 218

European-Non Finnish (NFE) AF: 0.864 AC: 45736 AN: 52954

Other (OTH) AF: 0.660 AC: 1001 AN: 1516

Alfa AF: 0.773 Hom.: 46523

Bravo AF: 0.619

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Benign:1

Aug 12, 2022

Dunham Lab, University of Washington

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Variant found at a frequency of over 32% in gnomAD (BA1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2472393; hg19: chrX-153771296;