rs202001697

chr10-102399458-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001322934.2(NFKB2):c.1288C>T(p.Pro430Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,508,150 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P430L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (8 hom.)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.21

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NFKB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.009656459).
• BP6: Variant 10-102399458-C-T is Benign according to our data. Variant chr10-102399458-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474775.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr10-102399458-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00121 (184/152358) while in subpopulation NFE AF= 0.00207 (141/68036). AF 95% confidence interval is 0.00179. There are 1 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB2	NM_001322934.2	c.1288C>T	p.Pro430Ser	missense_variant	13/23	ENST00000661543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB2	ENST00000661543.1	c.1288C>T	p.Pro430Ser	missense_variant	13/23		NM_001322934.2	P5

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152242 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000984 AC: 108 AN: 109778 Hom.: 1 AF XY: 0.000920 AC XY: 55 AN XY: 59794

Gnomad AFR exome AF: 0.000242

Gnomad AMR exome AF: 0.000417

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00184

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.000633

GnomAD4 exome AF: 0.00230 AC: 3116 AN: 1355792 Hom.: 8 Cov.: 35 AF XY: 0.00217 AC XY: 1445 AN XY: 665190

Gnomad4 AFR exome AF: 0.000244

Gnomad4 AMR exome AF: 0.000465

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000930

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.00275

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152358 Hom.: 1 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74506

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00306 Hom.: 0

Bravo AF: 0.00119

ExAC AF: 0.000346 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency, common variable, 10 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

NFKB2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

NFKB2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.0
Dann	Benign	0.88
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.60	T;T;.
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.15	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.011	.;B;.
Vest4		0.10
MVP		0.28
MPC		0.62
ClinPred		0.015	T
GERP RS		3.6
Varity_R		0.019
gMVP		0.27

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: rs202001697; hg19: chr10-104159215;