rs11574853

Positions:

• chr10-102402039-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001322934.2(NFKB2):​c.2467-9T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,569,874 control chromosomes in the GnomAD database, including 1,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (403 hom., cov: 33)
  • Exomes 𝑓: 0.022 (729 hom.)
• Consequence: NFKB2 NM_001322934.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004057
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.418

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-102402039-T-A is Benign according to our data. Variant chr10-102402039-T-A is described in ClinVar as [Benign]. Clinvar id is 403235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB2	NM_001322934.2	c.2467-9T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000661543.1	NP_001309863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1	c.2467-9T>A		splice_polypyrimidine_tract_variant, intron_variant			NM_001322934.2	ENSP00000499294	P5

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7626 AN: 152186 Hom.: 402 Cov.: 33

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0422

GnomAD3 exomes AF: 0.0264 AC: 4664 AN: 176834 Hom.: 158 AF XY: 0.0258 AC XY: 2434 AN XY: 94488

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.000469

Gnomad SAS exome AF: 0.0343

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.0212

Gnomad OTH exome AF: 0.0237

GnomAD4 exome AF: 0.0224 AC: 31738 AN: 1417570 Hom.: 729 Cov.: 34 AF XY: 0.0225 AC XY: 15776 AN XY: 701110

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0361

Gnomad4 EAS exome AF: 0.000375

Gnomad4 SAS exome AF: 0.0315

Gnomad4 FIN exome AF: 0.00372

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0302

GnomAD4 genome AF: 0.0502 AC: 7646 AN: 152304 Hom.: 403 Cov.: 33 AF XY: 0.0479 AC XY: 3567 AN XY: 74484

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0250

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0294

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.0291 Hom.: 39

Bravo AF: 0.0551

Asia WGS AF: 0.0210 AC: 76 AN: 3478

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.1
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.090
SpliceAI score (max)		0.050		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: rs11574853; hg19: chr10-104161796;