rs200227171

chr10-102400429-G-A

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.1736G>A(p.Arg579His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,612,766 control chromosomes in the GnomAD database, including 5 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R579C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (5 hom.)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.772

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=0.008429229).
• BP6: Variant 10-102400429-G-A is Benign according to our data. Variant chr10-102400429-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541630.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000637 (97/152298) while in subpopulation SAS AF= 0.00104 (5/4830). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB2	NM_001322934.2	c.1736G>A	p.Arg579His	missense_variant	16/23	ENST00000661543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB2	ENST00000661543.1	c.1736G>A	p.Arg579His	missense_variant	16/23		NM_001322934.2	P5

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000955 AC: 236 AN: 247026 Hom.: 2 AF XY: 0.000991 AC XY: 133 AN XY: 134274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00160

Gnomad NFE exome AF: 0.000884

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000694 AC: 1014 AN: 1460468 Hom.: 5 Cov.: 34 AF XY: 0.000764 AC XY: 555 AN XY: 726602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00609

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.000549

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74466

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.000548

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.000821 AC: 7

ExAC AF: 0.000966 AC: 117

EpiCase AF: 0.000763

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency, common variable, 10 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	NFKB2 NM_001077494.3 exon 16 p.Arg579His (c.1736G>A): This variant has not been reported in the literature but is present in 0.1% (41/30766) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs200227171). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

NFKB2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 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

Oct 01, 2022

NFKB2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.86	D;D;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;M;M
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.099	T;T;T
Polyphen		0.66	.;P;.
Vest4		0.29
MVP		0.57
MPC		0.76
ClinPred		0.027	T
GERP RS		0.50
Varity_R		0.066
gMVP		0.38

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: rs200227171; hg19: chr10-104160186; COSMIC: COSV50050536; COSMIC: COSV50050536;