10-102400748-G-T

Variant names:

• chr10-102400748-G-T
• rs757608785
• NM_001322934.2:c.1892G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001322934.2(NFKB2):​c.1892G>T​(p.Arg631Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R631W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30501497).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	NM_001322934.2	MANE Select	c.1892G>T	p.Arg631Leu	missense	Exon 17 of 23	NP_001309863.1
	NFKB2	NM_001077494.3		c.1892G>T	p.Arg631Leu	missense	Exon 17 of 23	NP_001070962.1
	NFKB2	NM_001261403.3		c.1892G>T	p.Arg631Leu	missense	Exon 16 of 22	NP_001248332.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	ENST00000661543.1	MANE Select	c.1892G>T	p.Arg631Leu	missense	Exon 17 of 23	ENSP00000499294.1
	NFKB2	ENST00000369966.8	TSL:1	c.1892G>T	p.Arg631Leu	missense	Exon 17 of 23	ENSP00000358983.3
	NFKB2	ENST00000189444.11	TSL:1	c.1892G>T	p.Arg631Leu	missense	Exon 17 of 23	ENSP00000189444.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

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	0.27
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.21
Sift	Benign	0.032	D
Sift4G	Benign	0.096	T
Polyphen		1.0	D
Vest4		0.33
MutPred		0.45		Loss of phosphorylation at T629 (P = 0.0593)
MVP		0.37
MPC		1.8
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.46
gMVP		0.65
Mutation Taster		=85/15	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: rs757608785; hg19: chr10-104160505;