10-102395963-G-A

Position:

• chr10-102395963-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001322934.2(NFKB2):​c.4G>A​(p.Glu2Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFKB2. . Gene score misZ 3.9376 (greater than the threshold 3.09). Trascript score misZ 3.5752 (greater than threshold 3.09). GenCC has associacion of gene with common variable immunodeficiency, deficiency in anterior pituitary function - variable immunodeficiency syndrome, immunodeficiency, common variable, 10.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19078878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB2	NM_001322934.2	c.4G>A	p.Glu2Lys	missense_variant	2/23	ENST00000661543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB2	ENST00000661543.1	c.4G>A	p.Glu2Lys	missense_variant	2/23		NM_001322934.2	P5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2019

This sequence change replaces glutamic acid with lysine at codon 2 of the NFKB2 protein (p.Glu2Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NFKB2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T;.;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.68	T;T;T;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L;L;.;L
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.71	.;N;N;.;N
REVEL	Benign	0.052
Sift	Uncertain	0.026	.;D;D;.;D
Sift4G	Pathogenic	0.0	D;T;T;D;T
Polyphen		0.034	.;.;B;.;.
Vest4		0.31, 0.31, 0.31
MutPred		0.22		Gain of ubiquitination at E2 (P = 0.0128);Gain of ubiquitination at E2 (P = 0.0128);Gain of ubiquitination at E2 (P = 0.0128);Gain of ubiquitination at E2 (P = 0.0128);Gain of ubiquitination at E2 (P = 0.0128);
MVP		0.39
MPC		1.4
ClinPred		0.67	D
GERP RS		3.5
Varity_R		0.38
gMVP		0.79

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: rs2061101667; hg19: chr10-104155720;