rs200296680

Variant names:

• chr8-42316223-C-T
• rs200296680
• NM_001556.3:c.814C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001556.3(IKBKB):​c.814C>T​(p.Arg272*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKBKB NM_001556.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.87
• Publications: 4 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-42316223-C-T is Pathogenic according to our data. Variant chr8-42316223-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 157663.Status of the report is criteria_provided_single_submitter, 1 stars.

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.814C>T	p.Arg272*	stop_gained	Exon 10 of 22	NP_001547.1	O14920-1
	IKBKB	NM_001242778.2		c.637C>T	p.Arg213*	stop_gained	Exon 9 of 21	NP_001229707.1	O14920-4
	IKBKB	NM_001190720.3		c.622C>T	p.Arg208*	stop_gained	Exon 9 of 21	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.814C>T	p.Arg272*	stop_gained	Exon 10 of 22	ENSP00000430684.1	O14920-1
	IKBKB	ENST00000523517.5	TSL:1	n.814C>T		non_coding_transcript_exon	Exon 9 of 21	ENSP00000430114.1	E5RGW5
	IKBKB	ENST00000957021.1		c.814C>T	p.Arg272*	stop_gained	Exon 10 of 22	ENSP00000627080.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Severe combined immunodeficiency due to IKK2 deficiency (1)
1	-	-	Severe combined immunodeficiency due to IKK2 deficiency;C4748694:Immunodeficiency 15a (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.68	D
PhyloP100		1.9
Vest4		0.96
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs200296680; hg19: chr8-42173741;