rs2061101667

Variant names:

• chr10-102395963-G-A
• rs2061101667
• NM_001322934.2:c.4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 13/22 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
• Publications: 0 publications found

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]

NFKB2 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 10

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• deficiency in anterior pituitary function - variable immunodeficiency syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19078878).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322934.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	NM_001322934.2	MANE Select	c.4G>A	p.Glu2Lys	missense	Exon 2 of 23	NP_001309863.1	Q00653-1
	NFKB2	NM_001077494.3		c.4G>A	p.Glu2Lys	missense	Exon 2 of 23	NP_001070962.1	Q00653-1
	NFKB2	NM_001261403.3		c.4G>A	p.Glu2Lys	missense	Exon 1 of 22	NP_001248332.1	Q00653-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	ENST00000661543.1	MANE Select	c.4G>A	p.Glu2Lys	missense	Exon 2 of 23	ENSP00000499294.1	Q00653-1
	NFKB2	ENST00000369966.8	TSL:1	c.4G>A	p.Glu2Lys	missense	Exon 2 of 23	ENSP00000358983.3	Q00653-1
	NFKB2	ENST00000189444.11	TSL:1	c.4G>A	p.Glu2Lys	missense	Exon 2 of 23	ENSP00000189444.6	Q00653-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency, common variable, 10 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.052
Sift	Uncertain	0.026	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.034	B
Vest4		0.31
MutPred		0.22		Gain of ubiquitination at E2 (P = 0.0128)
MVP		0.39
MPC		1.4
ClinPred		0.67	D
GERP RS		3.5
PromoterAI		-0.050	Neutral
Varity_R		0.38
gMVP		0.79
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs2061101667; hg19: chr10-104155720;