rs9694958

Variant names:

• chr8-42298528-A-G
• rs9694958
• NM_001556.3:c.388+5016A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001556.3(IKBKB):​c.388+5016A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 953,402 control chromosomes in the GnomAD database, including 17,367 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (9766 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7601 hom.)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 9 publications found

Genes affected

IKBKB (HGNC:5960): (inhibitor of nuclear factor kappa B kinase subunit beta) The protein encoded by this gene phosphorylates the inhibitor in the inhibitor/NF-kappa-B complex, causing dissociation of the inhibitor and activation of NF-kappa-B. The encoded protein itself is found in a complex of proteins. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Sep 2011]

IKBKB Gene-Disease associations (from GenCC):

• severe combined immunodeficiency due to IKK2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen
• immunodeficiency 15a

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

LOC105379395 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001556.3. 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
	IKBKB	NM_001556.3	MANE Select	c.388+5016A>G		intron	N/A	NP_001547.1	O14920-1
	IKBKB	NM_001242778.2		c.211+5016A>G		intron	N/A	NP_001229707.1	O14920-4
	IKBKB	NM_001190720.3		c.196+5016A>G		intron	N/A	NP_001177649.2	A0A499FJS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.388+5016A>G		intron	N/A	ENSP00000430684.1	O14920-1
	IKBKB	ENST00000519735.5	TSL:1	n.558+5016A>G		intron	N/A
	IKBKB	ENST00000523517.5	TSL:1	n.388+5016A>G		intron	N/A	ENSP00000430114.1	E5RGW5

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38521 AN: 152114 Hom.: 9719 Cov.: 33

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.105 AC: 83822 AN: 801170 Hom.: 7601 Cov.: 13 AF XY: 0.104 AC XY: 38569 AN XY: 370862

African (AFR) AF: 0.708 AC: 10904 AN: 15400

American (AMR) AF: 0.0907 AC: 86 AN: 948

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 234 AN: 4938

East Asian (EAS) AF: 0.146 AC: 508 AN: 3482

South Asian (SAS) AF: 0.236 AC: 3757 AN: 15920

European-Finnish (FIN) AF: 0.101 AC: 27 AN: 268

Middle Eastern (MID) AF: 0.137 AC: 214 AN: 1564

European-Non Finnish (NFE) AF: 0.0879 AC: 64392 AN: 732370

Other (OTH) AF: 0.141 AC: 3700 AN: 26280

GnomAD4 genome AF: 0.254 AC: 38620 AN: 152232 Hom.: 9766 Cov.: 33 AF XY: 0.252 AC XY: 18770 AN XY: 74462

African (AFR) AF: 0.657 AC: 27249 AN: 41498

American (AMR) AF: 0.135 AC: 2063 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

East Asian (EAS) AF: 0.148 AC: 768 AN: 5182

South Asian (SAS) AF: 0.238 AC: 1147 AN: 4826

European-Finnish (FIN) AF: 0.124 AC: 1314 AN: 10608

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0794 AC: 5403 AN: 68028

Other (OTH) AF: 0.206 AC: 436 AN: 2112

Alfa AF: 0.123 Hom.: 1342

Bravo AF: 0.268

Asia WGS AF: 0.285 AC: 991 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.24
DANN	Benign	0.41
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs9694958; hg19: chr8-42156046;