rs45581936

chr10-102396271-G-Achr10-102396271-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001322934.2(NFKB2):c.40G>A(p.Glu14Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000841 in 1,612,586 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (3 hom.)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.74

Genes affected

NFKB2 (HGNC:7795): (nuclear factor kappa B subunit 2) This gene encodes a subunit of the transcription factor complex nuclear factor-kappa-B (NFkB). The NFkB complex is expressed in numerous cell types and functions as a central activator of genes involved in inflammation and immune function. The protein encoded by this gene can function as both a transcriptional activator or repressor depending on its dimerization partner. The p100 full-length protein is co-translationally processed into a p52 active form. Chromosomal rearrangements and translocations of this locus have been observed in B cell lymphomas, some of which may result in the formation of fusion proteins. There is a pseudogene for this gene on chromosome 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NFKB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.006150514).
• BP6: Variant 10-102396271-G-A is Benign according to our data. Variant chr10-102396271-G-A is described in ClinVar as [Benign]. Clinvar id is 474786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102396271-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00405 (617/152224) while in subpopulation AFR AF= 0.0136 (566/41538). AF 95% confidence interval is 0.0127. There are 4 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 613 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB2	NM_001322934.2	c.40G>A	p.Glu14Lys	missense_variant	3/23	ENST00000661543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB2	ENST00000661543.1	c.40G>A	p.Glu14Lys	missense_variant	3/23		NM_001322934.2	P5

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152106 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00119 AC: 298 AN: 249404 Hom.: 2 AF XY: 0.000902 AC XY: 122 AN XY: 135302

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00547

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000506 AC: 739 AN: 1460362 Hom.: 3 Cov.: 33 AF XY: 0.000467 AC XY: 339 AN XY: 726134

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.000694

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00405 AC: 617 AN: 152224 Hom.: 4 Cov.: 31 AF XY: 0.00388 AC XY: 289 AN XY: 74420

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000778 Hom.: 0

Bravo AF: 0.00467

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0132 AC: 50

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00139 AC: 168

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.097	T;.;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.66	T;D;D;.;.
MetaRNN	Benign	0.0062	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.92	D;D;D;D
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.12	T;D;D;T;D
Polyphen		0.12	.;.;B;.;.
Vest4		0.31, 0.32, 0.31
MVP		0.52
MPC		1.4
ClinPred		0.024	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs45581936; hg19: chr10-104156028;