rs151057347

Variant names:

• chr8-42321909-A-C
• rs151057347
• NM_001556.3:c.1702A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001556.3(IKBKB):​c.1702A>C​(p.Arg568Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00239 in 1,610,070 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (10 hom.)
• Consequence: IKBKB NM_001556.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.66
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008109927).
• BP6: Variant 8-42321909-A-C is Benign according to our data. Variant chr8-42321909-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00185 (282/152318) while in subpopulation NFE AF = 0.00306 (208/68034). AF 95% confidence interval is 0.00272. There are 1 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR,AD gene

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.1702A>C	p.Arg568Arg	synonymous	Exon 17 of 22	NP_001547.1	O14920-1
	IKBKB	NM_001242778.2		c.1525A>C	p.Arg509Arg	synonymous	Exon 16 of 21	NP_001229707.1	O14920-4
	IKBKB	NM_001190720.3		c.1510A>C	p.Arg504Arg	synonymous	Exon 16 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.1702A>C	p.Arg568Arg	synonymous	Exon 17 of 22	ENSP00000430684.1	O14920-1
	IKBKB	ENST00000523517.5	TSL:1	n.*521A>C		non_coding_transcript_exon	Exon 16 of 21	ENSP00000430114.1	E5RGW5
	IKBKB	ENST00000523517.5	TSL:1	n.*521A>C		3_prime_UTR	Exon 16 of 21	ENSP00000430114.1	E5RGW5

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00172 AC: 427 AN: 247740 AF XY: 0.00168

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00246

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000697

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00244 AC: 3559 AN: 1457752 Hom.: 10 Cov.: 30 AF XY: 0.00246 AC XY: 1786 AN XY: 725362

African (AFR) AF: 0.000513 AC: 17 AN: 33154

American (AMR) AF: 0.00207 AC: 90 AN: 43540

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 72 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000931 AC: 8 AN: 85916

European-Finnish (FIN) AF: 0.000787 AC: 42 AN: 53346

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5728

European-Non Finnish (NFE) AF: 0.00279 AC: 3102 AN: 1110410

Other (OTH) AF: 0.00364 AC: 219 AN: 60150

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74494

African (AFR) AF: 0.000361 AC: 15 AN: 41568

American (AMR) AF: 0.00261 AC: 40 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00233 Hom.: 0

Bravo AF: 0.00184

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00159 AC: 193

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	-0.49	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0066	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0081	T
PhyloP100		5.7
Vest4		0.22
MVP		0.86
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs151057347; hg19: chr8-42179427;