8-42271987-A-T

Variant names:

• chr8-42271987-A-T
• rs3747811
• NM_001556.3:c.-18-96A>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.-18-96A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,257,516 control chromosomes in the GnomAD database, including 142,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13469 hom., cov: 33)
  • Exomes 𝑓: 0.48 (129374 hom.)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.25
• Publications: 23 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=-0.9).
• BP6: Variant 8-42271987-A-T is Benign according to our data. Variant chr8-42271987-A-T is described in ClinVar as Benign. ClinVar VariationId is 1266286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKB	NM_001556.3	c.-18-96A>T		intron_variant	Intron 1 of 21	ENST00000520810.6	NP_001547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6	c.-18-96A>T		intron_variant	Intron 1 of 21	1	NM_001556.3	ENSP00000430684.1

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59334 AN: 152056 Hom.: 13458 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.417

GnomAD4 exome AF: 0.479 AC: 529792 AN: 1105342 Hom.: 129374 Cov.: 14 AF XY: 0.480 AC XY: 265237 AN XY: 552238

African (AFR) AF: 0.128 AC: 3145 AN: 24580

American (AMR) AF: 0.607 AC: 16291 AN: 26818

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 8688 AN: 18362

East Asian (EAS) AF: 0.511 AC: 19116 AN: 37396

South Asian (SAS) AF: 0.481 AC: 30555 AN: 63478

European-Finnish (FIN) AF: 0.432 AC: 20759 AN: 48050

Middle Eastern (MID) AF: 0.448 AC: 1481 AN: 3308

European-Non Finnish (NFE) AF: 0.488 AC: 407670 AN: 836038

Other (OTH) AF: 0.467 AC: 22087 AN: 47312

GnomAD4 genome AF: 0.390 AC: 59355 AN: 152174 Hom.: 13469 Cov.: 33 AF XY: 0.393 AC XY: 29264 AN XY: 74384

African (AFR) AF: 0.142 AC: 5888 AN: 41552

American (AMR) AF: 0.536 AC: 8194 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1680 AN: 3470

East Asian (EAS) AF: 0.562 AC: 2915 AN: 5186

South Asian (SAS) AF: 0.481 AC: 2322 AN: 4826

European-Finnish (FIN) AF: 0.429 AC: 4536 AN: 10566

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32346 AN: 67978

Other (OTH) AF: 0.415 AC: 873 AN: 2106

Alfa AF: 0.321 Hom.: 1051

Bravo AF: 0.391

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

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 67% of patients studied by a panel of primary immunodeficiencies. Number of patients: 64. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.046
DANN	Benign	0.52
PhyloP100		-1.3
PromoterAI		0.046	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3747811; hg19: chr8-42129505;