chr10-102399455-A-G

Position:

• chr10-102399455-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001322934.2(NFKB2):​c.1285A>G​(p.Thr429Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,360,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000022 (0 hom.)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.96

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 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=0.043348312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB2	NM_001322934.2	c.1285A>G	p.Thr429Ala	missense_variant	13/23	ENST00000661543.1	NP_001309863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1	c.1285A>G	p.Thr429Ala	missense_variant	13/23		NM_001322934.2	ENSP00000499294	P5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000888 AC: 1 AN: 112550 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 61214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1360500 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 668208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000283

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 12, 2022

This variant has not been reported in the literature in individuals affected with NFKB2-related conditions. 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 429 of the NFKB2 protein (p.Thr429Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.10
DANN	Benign	0.44
DEOGEN2	Benign	0.070	.;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.30	T;T;.
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.83	N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.0020
Sift	Benign	0.81	T;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.10
MutPred		0.23		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);
MVP		0.25
MPC		0.60
ClinPred		0.045	T
GERP RS		-6.0
Varity_R		0.028
gMVP		0.23

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

Other links and lift over

dbSNP: rs1405716353; hg19: chr10-104159212;