NM_001556.3:c.1986+704C>T

Variant names:

• chr8-42323198-C-T
• rs10958713
• NM_001556.3:c.1986+704C>T

Variant summary

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

The NM_001556.3(IKBKB):​c.1986+704C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,216 control chromosomes in the GnomAD database, including 7,995 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 0.29 (7995 hom., cov: 33)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 29 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	NM_001556.3	MANE Select	c.1986+704C>T		intron	N/A	NP_001547.1
	IKBKB	NM_001242778.2		c.1809+704C>T		intron	N/A	NP_001229707.1
	IKBKB	NM_001190720.3		c.1794+704C>T		intron	N/A	NP_001177649.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.1986+704C>T		intron	N/A	ENSP00000430684.1
	IKBKB	ENST00000523517.5	TSL:1	n.*805+704C>T		intron	N/A	ENSP00000430114.1
	IKBKB	ENST00000520835.7	TSL:2	c.1794+704C>T		intron	N/A	ENSP00000430868.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43846 AN: 152096 Hom.: 7985 Cov.: 33

Gnomad AFR AF: 0.0745

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.309

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

GnomAD4 genome AF: 0.288 AC: 43865 AN: 152216 Hom.: 7995 Cov.: 33 AF XY: 0.291 AC XY: 21664 AN XY: 74402

African (AFR) AF: 0.0743 AC: 3090 AN: 41564

American (AMR) AF: 0.454 AC: 6941 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1297 AN: 3472

East Asian (EAS) AF: 0.540 AC: 2792 AN: 5166

South Asian (SAS) AF: 0.439 AC: 2118 AN: 4822

European-Finnish (FIN) AF: 0.256 AC: 2713 AN: 10588

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23864 AN: 67996

Other (OTH) AF: 0.309 AC: 651 AN: 2110

Alfa AF: 0.352 Hom.: 20302

Bravo AF: 0.298

Asia WGS AF: 0.408 AC: 1417 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.93
DANN	Benign	0.45
PhyloP100		0.0050
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: rs10958713; hg19: chr8-42180716;