rs201623844

Positions:

• chr10-102400818-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001322934.2(NFKB2):​c.1962C>T​(p.Val654=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,592,402 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (11 hom.)
• Consequence: NFKB2 NM_001322934.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.332

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 10-102400818-C-T is Benign according to our data. Variant chr10-102400818-C-T is described in ClinVar as [Benign]. Clinvar id is 474779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102400818-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00216 (328/151722) while in subpopulation NFE AF= 0.00289 (196/67922). AF 95% confidence interval is 0.00255. There are 1 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB2	NM_001322934.2	c.1962C>T	p.Val654=	synonymous_variant	17/23	ENST00000661543.1	NP_001309863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1	c.1962C>T	p.Val654=	synonymous_variant	17/23		NM_001322934.2	ENSP00000499294	P5

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 151604 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00289

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00260 AC: 570 AN: 219630 Hom.: 1 AF XY: 0.00247 AC XY: 292 AN XY: 118458

Gnomad AFR exome AF: 0.000437

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000320

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00308 AC: 4444 AN: 1440680 Hom.: 11 Cov.: 39 AF XY: 0.00309 AC XY: 2205 AN XY: 714104

Gnomad4 AFR exome AF: 0.000450

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000459

Gnomad4 NFE exome AF: 0.00329

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.00216 AC: 328 AN: 151722 Hom.: 1 Cov.: 32 AF XY: 0.00197 AC XY: 146 AN XY: 74114

Gnomad4 AFR AF: 0.000508

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.00289

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00386 Hom.: 2

Bravo AF: 0.00223

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

NFKB2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2019

This variant is classified as 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

Sep 01, 2022

NFKB2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs201623844; hg19: chr10-104160575;