10-102402138-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001322934.2(NFKB2):c.2557C>T(p.Arg853Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R853R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NFKB2 NM_001322934.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 0.458

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102402138-C-T is Pathogenic according to our data. Variant chr10-102402138-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 65385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102402138-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB2	NM_001322934.2	c.2557C>T	p.Arg853Ter	stop_gained	22/23	ENST00000661543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB2	ENST00000661543.1	c.2557C>T	p.Arg853Ter	stop_gained	22/23		NM_001322934.2	P5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1425178 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 705554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 10 Pathogenic:8

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Bioinformatics Unit, Institut Pasteur de Montevideo	Sep 05, 2023	We found this variant in three affected family members and not present in an unaffected one. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Diagnostics Genetics, LabPLUS - Auckland City Hospital	Sep 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	This sequence change creates a premature translational stop signal (p.Arg853*) in the NFKB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the NFKB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with NFKB2-related immunodeficiencies (PMID: 24702956, 25524009, 25605273). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65385). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NFKB2 function (PMID: 24140114, 28778864). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000065385 / PMID: 24140114). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	research	Samuels research lab, Centre de Recherche du CHU Ste-Justine	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 48 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); In vitro assays demonstrated that R853X has a dominant negative effect (Kuehn et al., 2017); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24702956, 25605273, 27577878, 28778864, 28983403, 29225085, 30941118, 30078247, 28919517, 30267444, 24140114, 25524009, 30500415, 29952021, 32135276, 32499645, 32888943, 32694887) -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 15, 2016

- -

Inherited Immunodeficiency Diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2019

- -

Common variable immunodeficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 09, 2020

Variant summary: NFKB2 c.2557C>T (p.Arg853X) results in a premature termination codon, and though it is not expected to cause nonsense mediated decay (NMD), it is predicted to cause a truncation of the encoded protein. The variant was absent in 187640 control chromosomes (gnomAD). c.2557C>T has been reported in the literature in numerous individuals affected with Common Variable Immunodeficiency (e.g. Chen_2013, Klemann_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this C-terminal truncation indeed affects normal protein function (Chen_2013, Kuehn_2017). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.18	N
MutationTaster	Benign	1.0	D;D;D;D
Vest4		0.89
GERP RS		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397514332; hg19: chr10-104161895;