Genetic Variant NM_001322934.2:c.2557C>G (chr10-102402138-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001322934.2(NFKB2):c.2557C>G(p.Arg853Gly) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

NFKB2
NM_001322934.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.458

Publications

19 publications found

Variant links:

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

NFKB2 links:

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ACMG classification

Classification was made for transcript

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=0.07561013).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NFKB2	NM_001322934.2	MANE Select	c.2557C>G	p.Arg853Gly	missense	Exon 22 of 23	NP_001309863.1
NFKB2	NM_001077494.3		c.2557C>G	p.Arg853Gly	missense	Exon 22 of 23	NP_001070962.1
NFKB2	NM_001261403.3		c.2557C>G	p.Arg853Gly	missense	Exon 21 of 22	NP_001248332.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NFKB2	ENST00000661543.1	MANE Select	c.2557C>G	p.Arg853Gly	missense	Exon 22 of 23	ENSP00000499294.1
NFKB2	ENST00000369966.8	TSL:1	c.2557C>G	p.Arg853Gly	missense	Exon 22 of 23	ENSP00000358983.3
NFKB2	ENST00000189444.11	TSL:1	c.2557C>G	p.Arg853Gly	missense	Exon 22 of 23	ENSP00000189444.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000533

AC:

AN:

187640

AF XY:

0.00000992

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000730

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.28

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.79

M_CAP

Benign

0.021

MetaRNN

Benign

0.076

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.46

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

REVEL

Benign

0.023

Sift

Benign

0.27

Sift4G

Benign

0.42

Polyphen

0.20

Vest4

0.22

MutPred

0.22

Gain of relative solvent accessibility (P = 0.0479)

MVP

0.31

MPC

0.79

ClinPred

0.068

GERP RS

2.0

Varity_R

0.10

gMVP

0.40

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over