NM_001322934.2:c.2594A>G

Variant names:

• chr10-102402267-A-G
• rs727502787
• NM_001322934.2:c.2594A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PS3 PM1 PM2 PP5_Moderate BP4

The NM_001322934.2(NFKB2):​c.2594A>G​(p.Asp865Gly) 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. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV006077099: In vitro functional expression studies in HEK293 cells showed that the mutation resulted in near absence of proper phosphorylation and processing of NFKB2 p100 to p52 in response to MAP3K14 and decreased nuclear translocation of p65 (Lee CE, et al., 2014).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.12
• Publications: 15 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006077099: In vitro functional expression studies in HEK293 cells showed that the mutation resulted in near absence of proper phosphorylation and processing of NFKB2 p100 to p52 in response to MAP3K14 and decreased nuclear translocation of p65 (Lee CE, et al., 2014).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001322934.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102402267-A-G is Pathogenic according to our data. Variant chr10-102402267-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 155765.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36893588). . Strength limited to SUPPORTING due to the PP5.

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.2594A>G	p.Asp865Gly	missense	Exon 23 of 23	NP_001309863.1	Q00653-1
	NFKB2	NM_001077494.3		c.2594A>G	p.Asp865Gly	missense	Exon 23 of 23	NP_001070962.1	Q00653-1
	NFKB2	NM_001261403.3		c.2591A>G	p.Asp864Gly	missense	Exon 22 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.2594A>G	p.Asp865Gly	missense	Exon 23 of 23	ENSP00000499294.1	Q00653-1
	NFKB2	ENST00000369966.8	TSL:1	c.2594A>G	p.Asp865Gly	missense	Exon 23 of 23	ENSP00000358983.3	Q00653-1
	NFKB2	ENST00000189444.11	TSL:1	c.2591A>G	p.Asp864Gly	missense	Exon 23 of 23	ENSP00000189444.6	Q00653-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
3	-	-	Immunodeficiency, common variable, 10 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.90	L
PhyloP100		7.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.32		Gain of loop (P = 0.0502)
MVP		0.70
MPC		1.8
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.30
gMVP		0.74
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs727502787; hg19: chr10-104162024;