rs2272736

Variant names:

• chr8-42319645-G-A
• rs2272736
• NM_001556.3:c.1577G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000520810.6(IKBKB):​c.1577G>A​(p.Arg526Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0038 in 1,586,780 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R526W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (292 hom.)
• Consequence: IKBKB ENST00000520810.6 missense, splice_region
• Scores: Splicing: ADA: 0.7745
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.80
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016427338).
• BP6: Variant 8-42319645-G-A is Benign according to our data. Variant chr8-42319645-G-A is described in ClinVar as Benign. ClinVar VariationId is 474791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000520810.6. 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.1577G>A	p.Arg526Gln	missense splice_region	Exon 15 of 22	NP_001547.1
	IKBKB	NM_001242778.2		c.1400G>A	p.Arg467Gln	missense splice_region	Exon 14 of 21	NP_001229707.1
	IKBKB	NM_001190720.3		c.1385G>A	p.Arg462Gln	missense splice_region	Exon 14 of 21	NP_001177649.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.1577G>A	p.Arg526Gln	missense splice_region	Exon 15 of 22	ENSP00000430684.1
	IKBKB	ENST00000523517.5	TSL:1	n.*396G>A		splice_region non_coding_transcript_exon	Exon 14 of 21	ENSP00000430114.1
	IKBKB	ENST00000523517.5	TSL:1	n.*396G>A		3_prime_UTR	Exon 14 of 21	ENSP00000430114.1

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152040 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00897 AC: 2040 AN: 227334 AF XY: 0.00862

Gnomad AFR exome AF: 0.000949

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.114

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00494

GnomAD4 exome AF: 0.00372 AC: 5343 AN: 1434622 Hom.: 292 Cov.: 31 AF XY: 0.00367 AC XY: 2615 AN XY: 712498

African (AFR) AF: 0.000537 AC: 17 AN: 31644

American (AMR) AF: 0.000189 AC: 7 AN: 37050

Ashkenazi Jewish (ASJ) AF: 0.000201 AC: 5 AN: 24854

East Asian (EAS) AF: 0.118 AC: 4639 AN: 39472

South Asian (SAS) AF: 0.00330 AC: 268 AN: 81216

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53046

Middle Eastern (MID) AF: 0.000997 AC: 5 AN: 5016

European-Non Finnish (NFE) AF: 0.0000508 AC: 56 AN: 1103180

Other (OTH) AF: 0.00583 AC: 345 AN: 59144

GnomAD4 genome AF: 0.00451 AC: 686 AN: 152158 Hom.: 23 Cov.: 32 AF XY: 0.00526 AC XY: 391 AN XY: 74386

African (AFR) AF: 0.00125 AC: 52 AN: 41512

American (AMR) AF: 0.000458 AC: 7 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.113 AC: 586 AN: 5176

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4816

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00364 Hom.: 77

Bravo AF: 0.00549

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00888 AC: 1078

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Severe combined immunodeficiency due to IKK2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.0025
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.14
Sift	Benign	0.46	T
Sift4G	Benign	0.84	T
Polyphen		0.064	B
Vest4		0.072
MVP		0.81
MPC		0.50
ClinPred		0.017	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.45
Mutation Taster		=35/65	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.48
Splicevardb		2.0
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: rs2272736; hg19: chr8-42177163; COSMIC: COSV60596127; COSMIC: COSV60596127;