8-42321909-A-C

Position:

• chr8-42321909-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001556.3(IKBKB):​c.1702A>C​(p.Arg568=) 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:4
• Conservation: PhyloP100: 5.66

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 -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 [Likely_benign]. Clinvar id is 474792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42321909-A-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKB	NM_001556.3	c.1702A>C	p.Arg568=	synonymous_variant	17/22	ENST00000520810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKB	ENST00000520810.6	c.1702A>C	p.Arg568=	synonymous_variant	17/22	1	NM_001556.3	P1

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

GnomAD3 exomes AF: 0.00172 AC: 427 AN: 247740 Hom.: 1 AF XY: 0.00168 AC XY: 225 AN XY: 134032

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 SAS exome AF: 0.0000330

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

Gnomad4 AFR exome AF: 0.000513

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.000787

Gnomad4 NFE exome AF: 0.00279

Gnomad4 OTH exome AF: 0.00364

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

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00189

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	IKBKB: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Severe combined immunodeficiency due to IKK2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	D;D;D;D;D
Vest4		0.22
MVP		0.86
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs151057347; hg19: chr8-42179427;