rs151151310

chr8-42314367-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001556.3(IKBKB):c.738C>T(p.Ser246=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,613,986 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (2 hom.)
• Consequence: IKBKB NM_001556.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0750

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 8-42314367-C-T is Benign according to our data. Variant chr8-42314367-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 541647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42314367-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.075 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000729 (111/152268) while in subpopulation AMR AF= 0.00425 (65/15294). AF 95% confidence interval is 0.00342. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKB	NM_001556.3	c.738C>T	p.Ser246=	synonymous_variant	9/22	ENST00000520810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKB	ENST00000520810.6	c.738C>T	p.Ser246=	synonymous_variant	9/22	1	NM_001556.3	P1

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 111 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000433 AC: 109 AN: 251492 Hom.: 0 AF XY: 0.000412 AC XY: 56 AN XY: 135920

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000703

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000781 AC: 1142 AN: 1461718 Hom.: 2 Cov.: 29 AF XY: 0.000787 AC XY: 572 AN XY: 727180

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000950

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74438

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000769 Hom.: 0

Bravo AF: 0.00147

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

IKBKB: BP4, BP7 -

Severe combined immunodeficiency due to IKK2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	9.4
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs151151310; hg19: chr8-42171885;