NM_001322934.2:c.1296C>G

Variant names:

• chr10-102399466-C-G
• rs192635220
• NM_001322934.2:c.1296C>G

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.1296C>G​(p.Cys432Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,349,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C432C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.544
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089241475).

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.1296C>G	p.Cys432Trp	missense	Exon 13 of 23	NP_001309863.1
	NFKB2	NM_001077494.3		c.1296C>G	p.Cys432Trp	missense	Exon 13 of 23	NP_001070962.1
	NFKB2	NM_001261403.3		c.1296C>G	p.Cys432Trp	missense	Exon 12 of 22	NP_001248332.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	ENST00000661543.1	MANE Select	c.1296C>G	p.Cys432Trp	missense	Exon 13 of 23	ENSP00000499294.1
	NFKB2	ENST00000369966.8	TSL:1	c.1296C>G	p.Cys432Trp	missense	Exon 13 of 23	ENSP00000358983.3
	NFKB2	ENST00000189444.11	TSL:1	c.1296C>G	p.Cys432Trp	missense	Exon 13 of 23	ENSP00000189444.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1349372 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 661506

African (AFR) AF: 0.00 AC: 0 AN: 28404

American (AMR) AF: 0.00 AC: 0 AN: 29218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22266

East Asian (EAS) AF: 0.00 AC: 0 AN: 33586

South Asian (SAS) AF: 0.00 AC: 0 AN: 74052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5190

European-Non Finnish (NFE) AF: 9.48e-7 AC: 1 AN: 1055094

Other (OTH) AF: 0.00 AC: 0 AN: 55644

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.54
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.020
Sift	Uncertain	0.019	D
Sift4G	Benign	0.096	T
Polyphen		0.0040	B
Vest4		0.19
MutPred		0.27		Gain of glycosylation at P434 (P = 0.1421)
MVP		0.11
MPC		0.90
ClinPred		0.17	T
GERP RS		0.039
Varity_R		0.28
gMVP		0.28
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: rs192635220; hg19: chr10-104159223; COSMIC: COSV50041802; COSMIC: COSV50041802;