NM_001322934.2:c.395+99A>G

Variant names:

• chr10-102397154-A-G
• rs12772374
• NM_001322934.2:c.395+99A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001322934.2(NFKB2):​c.395+99A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,559,794 control chromosomes in the GnomAD database, including 22,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1605 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20625 hom.)
• Consequence: NFKB2 NM_001322934.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.678
• Publications: 12 publications found

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]

NFKB2 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 10

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• deficiency in anterior pituitary function - variable immunodeficiency syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-102397154-A-G is Benign according to our data. Variant chr10-102397154-A-G is described in ClinVar as Benign. ClinVar VariationId is 2628274.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB2	NM_001322934.2	c.395+99A>G		intron_variant	Intron 6 of 22	ENST00000661543.1	NP_001309863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1	c.395+99A>G		intron_variant	Intron 6 of 22		NM_001322934.2	ENSP00000499294.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20096 AN: 152092 Hom.: 1610 Cov.: 32

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.0673

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.166 AC: 234134 AN: 1407584 Hom.: 20625 Cov.: 30 AF XY: 0.164 AC XY: 113822 AN XY: 695118

African (AFR) AF: 0.0404 AC: 1302 AN: 32242

American (AMR) AF: 0.103 AC: 4129 AN: 40134

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3414 AN: 23340

East Asian (EAS) AF: 0.166 AC: 6469 AN: 39080

South Asian (SAS) AF: 0.0655 AC: 5236 AN: 79934

European-Finnish (FIN) AF: 0.199 AC: 10136 AN: 50838

Middle Eastern (MID) AF: 0.125 AC: 588 AN: 4694

European-Non Finnish (NFE) AF: 0.179 AC: 193619 AN: 1079380

Other (OTH) AF: 0.159 AC: 9241 AN: 57942

GnomAD4 genome AF: 0.132 AC: 20096 AN: 152210 Hom.: 1605 Cov.: 32 AF XY: 0.132 AC XY: 9791 AN XY: 74408

African (AFR) AF: 0.0450 AC: 1869 AN: 41548

American (AMR) AF: 0.118 AC: 1801 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3472

East Asian (EAS) AF: 0.186 AC: 963 AN: 5176

South Asian (SAS) AF: 0.0665 AC: 321 AN: 4828

European-Finnish (FIN) AF: 0.206 AC: 2179 AN: 10594

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12024 AN: 67984

Other (OTH) AF: 0.134 AC: 284 AN: 2112

Alfa AF: 0.159 Hom.: 270

Bravo AF: 0.122

Asia WGS AF: 0.114 AC: 394 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.1
DANN	Benign	0.39
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12772374; hg19: chr10-104156911;