10-102399432-C-T

Position:

chr10-102399432-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP2BP4_StrongBS1_SupportingBS2

The NM_001322934.2(NFKB2):c.1262C>T(p.Ala421Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,367,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

NFKB2
NM_001322934.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.242

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 links:

NFKB2 (HGNC:):

NFKB2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFKB2. . Gene score misZ 3.9376 (greater than the threshold 3.09). Trascript score misZ 3.5752 (greater than threshold 3.09). GenCC has associacion of gene with common variable immunodeficiency, deficiency in anterior pituitary function - variable immunodeficiency syndrome, immunodeficiency, common variable, 10.

BP4

Computational evidence support a benign effect (MetaRNN=0.054190606).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000366 (5/1367724) while in subpopulation MID AF= 0.000402 (2/4980). AF 95% confidence interval is 0.0000709. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB2	NM_001322934.2 linkuse as main transcript	c.1262C>T	p.Ala421Val	missense_variant	13/23	ENST00000661543.1	NP_001309863.1	Q00653-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1 linkuse as main transcript	c.1262C>T	p.Ala421Val	missense_variant	13/23		NM_001322934.2	ENSP00000499294.1		Q00653-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

117920

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

64064

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000234

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000366

AC:

AN:

1367724

Hom.:

Cov.:

AF XY:

0.00000595

AC XY:

AN XY:

672484

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000579

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000119

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 579056). This variant has not been reported in the literature in individuals affected with NFKB2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 421 of the NFKB2 protein (p.Ala421Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.4

DANN

Uncertain

0.98

DEOGEN2

Benign

0.087

.;T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.60

T;T;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L;L

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.20

N;N;N

REVEL

Benign

0.0080

Sift

Benign

0.26

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.19

.;B;.

Vest4

0.094

MutPred

0.15

Loss of glycosylation at P426 (P = 0.1273);Loss of glycosylation at P426 (P = 0.1273);Loss of glycosylation at P426 (P = 0.1273);

MVP

0.22

MPC

0.61

ClinPred

0.028

GERP RS

1.9

Varity_R

0.025

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over