chr8-42300384-T-C

Variant names:

• chr8-42300384-T-C
• rs2272733
• NM_001556.3:c.389-4803T>C

Variant summary

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

The NM_001556.3(IKBKB):​c.389-4803T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 152,090 control chromosomes in the GnomAD database, including 43,900 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 0.72 (43900 hom., cov: 32)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0720
• Publications: 32 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, ClinGen, Ambry Genetics
• immunodeficiency 15a

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

LOC105379395 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKB	NM_001556.3	c.389-4803T>C		intron_variant	Intron 5 of 21	ENST00000520810.6	NP_001547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6	c.389-4803T>C		intron_variant	Intron 5 of 21	1	NM_001556.3	ENSP00000430684.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109670 AN: 151970 Hom.: 43888 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.938

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.916

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.885

Gnomad OTH AF: 0.773

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

GnomAD4 genome AF: 0.721 AC: 109696 AN: 152090 Hom.: 43900 Cov.: 32 AF XY: 0.722 AC XY: 53667 AN XY: 74356

African (AFR) AF: 0.338 AC: 14021 AN: 41422

American (AMR) AF: 0.848 AC: 12965 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 3179 AN: 3472

East Asian (EAS) AF: 0.854 AC: 4414 AN: 5166

South Asian (SAS) AF: 0.747 AC: 3598 AN: 4814

European-Finnish (FIN) AF: 0.811 AC: 8579 AN: 10580

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.885 AC: 60206 AN: 68024

Other (OTH) AF: 0.772 AC: 1633 AN: 2114

Alfa AF: 0.835 Hom.: 169942

Bravo AF: 0.712

Asia WGS AF: 0.707 AC: 2456 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.5
DANN	Benign	0.77
PhyloP100		-0.072
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: rs2272733; hg19: chr8-42157902;