chr8-42316862-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001556.3(IKBKB):c.1083G>A(p.Leu361Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0128 in 1,614,106 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 4 hom., cov: 32)

Exomes 𝑓: 0.013 ( 181 hom. )

Consequence

IKBKB
NM_001556.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.06

Publications

6 publications found

Variant links:

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)

IKBKB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 8-42316862-G-A is Benign according to our data. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42316862-G-A is described in CliVar as Benign. Clinvar id is 474788.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 = 0.00977 (1488/152284) while in subpopulation NFE AF = 0.0169 (1150/68030). AF 95% confidence interval is 0.0161. There are 4 homozygotes in GnomAd4. There are 668 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKB	NM_001556.3 link	c.1083G>A	p.Leu361Leu	synonymous_variant	Exon 11 of 22	ENST00000520810.6	NP_001547.1	O14920-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6 link	c.1083G>A	p.Leu361Leu	synonymous_variant	Exon 11 of 22	1	NM_001556.3	ENSP00000430684.1		O14920-1

Frequencies

GnomAD3 genomes

AF:

0.00978

AC:

1488

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00925

AC:

2323

AN:

251040

AF XY:

0.00885

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0153

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.00915

GnomAD4 exome

AF:

0.0131

AC:

19185

AN:

1461822

Hom.:

181

Cov.:

AF XY:

0.0126

AC XY:

9176

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33480

American (AMR)

AF:

0.00235

AC:

105

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0158

AC:

843

AN:

53396

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0157

AC:

17510

AN:

1111986

Other (OTH)

AF:

0.00985

AC:

595

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1062

2123

3185

4246

5308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

642

1284

1926

2568

3210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00977

AC:

1488

AN:

152284

Hom.:

Cov.:

AF XY:

0.00897

AC XY:

668

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00250

AC:

104

AN:

41556

American (AMR)

AF:

0.00419

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0137

AC:

145

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1150

AN:

68030

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

160

239

319

399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0136

Hom.:

Bravo

AF:

0.00875

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Severe combined immunodeficiency due to IKK2 deficiency

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.2

(source)

DANN

Benign

0.41

PhyloP100

4.1

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over