chr8-42317785-A-T

Variant names:

• chr8-42317785-A-T
• rs2294100
• NM_001556.3:c.1240+14A>T

Variant summary

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

The NM_001556.3(IKBKB):​c.1240+14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.888 in 1,568,716 control chromosomes in the GnomAD database, including 630,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (48206 hom., cov: 31)
  • Exomes 𝑓: 0.90 (582323 hom.)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.318
• Publications: 11 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 (BayesDel_noAF=-0.81).
• BP6: Variant 8-42317785-A-T is Benign according to our data. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42317785-A-T is described in CliVar as Benign. Clinvar id is 402969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKB	NM_001556.3	c.1240+14A>T		intron_variant	Intron 12 of 21	ENST00000520810.6	NP_001547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6	c.1240+14A>T		intron_variant	Intron 12 of 21	1	NM_001556.3	ENSP00000430684.1

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115777 AN: 151934 Hom.: 48188 Cov.: 31

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.945

Gnomad AMR AF: 0.885

Gnomad ASJ AF: 0.936

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.803

GnomAD2 exomes AF: 0.863 AC: 216727 AN: 251264 AF XY: 0.868

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.930

Gnomad ASJ exome AF: 0.935

Gnomad EAS exome AF: 0.876

Gnomad FIN exome AF: 0.833

Gnomad NFE exome AF: 0.928

Gnomad OTH exome AF: 0.886

GnomAD4 exome AF: 0.902 AC: 1277563 AN: 1416664 Hom.: 582323 Cov.: 24 AF XY: 0.900 AC XY: 637255 AN XY: 707980

African (AFR) AF: 0.376 AC: 12197 AN: 32402

American (AMR) AF: 0.925 AC: 41301 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.934 AC: 24170 AN: 25888

East Asian (EAS) AF: 0.853 AC: 33651 AN: 39448

South Asian (SAS) AF: 0.789 AC: 67310 AN: 85282

European-Finnish (FIN) AF: 0.841 AC: 44882 AN: 53380

Middle Eastern (MID) AF: 0.884 AC: 5031 AN: 5692

European-Non Finnish (NFE) AF: 0.931 AC: 997490 AN: 1071004

Other (OTH) AF: 0.875 AC: 51531 AN: 58898

GnomAD4 genome AF: 0.762 AC: 115822 AN: 152052 Hom.: 48206 Cov.: 31 AF XY: 0.760 AC XY: 56477 AN XY: 74330

African (AFR) AF: 0.393 AC: 16282 AN: 41410

American (AMR) AF: 0.886 AC: 13540 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.936 AC: 3247 AN: 3470

East Asian (EAS) AF: 0.854 AC: 4420 AN: 5176

South Asian (SAS) AF: 0.778 AC: 3756 AN: 4826

European-Finnish (FIN) AF: 0.819 AC: 8646 AN: 10556

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.928 AC: 63122 AN: 68014

Other (OTH) AF: 0.802 AC: 1691 AN: 2108

Alfa AF: 0.856 Hom.: 10682

Bravo AF: 0.754

Asia WGS AF: 0.729 AC: 2533 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. Only high quality variants are reported. -

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Immunodeficiency 15a Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.81
CADD	Benign	3.6
DANN	Benign	0.67
PhyloP100		-0.32
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2294100; hg19: chr8-42175303;