NM_001322934.2:c.1269A>T

Variant names:

• chr10-102399439-A-T
• rs4919633
• NM_001322934.2:c.1269A>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001322934.2(NFKB2):​c.1269A>T​(p.Pro423Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000734 in 1,362,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P423P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NFKB2 NM_001322934.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0690
• Publications: 18 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=0.069 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322934.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	NM_001322934.2	MANE Select	c.1269A>T	p.Pro423Pro	synonymous	Exon 13 of 23	NP_001309863.1
	NFKB2	NM_001077494.3		c.1269A>T	p.Pro423Pro	synonymous	Exon 13 of 23	NP_001070962.1
	NFKB2	NM_001261403.3		c.1269A>T	p.Pro423Pro	synonymous	Exon 12 of 22	NP_001248332.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	ENST00000661543.1	MANE Select	c.1269A>T	p.Pro423Pro	synonymous	Exon 13 of 23	ENSP00000499294.1
	NFKB2	ENST00000369966.8	TSL:1	c.1269A>T	p.Pro423Pro	synonymous	Exon 13 of 23	ENSP00000358983.3
	NFKB2	ENST00000189444.11	TSL:1	c.1269A>T	p.Pro423Pro	synonymous	Exon 13 of 23	ENSP00000189444.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1362756 Hom.: 0 Cov.: 80 AF XY: 0.00000149 AC XY: 1 AN XY: 669556

African (AFR) AF: 0.00 AC: 0 AN: 29158

American (AMR) AF: 0.00 AC: 0 AN: 30508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23160

East Asian (EAS) AF: 0.00 AC: 0 AN: 34360

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4968

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061576

Other (OTH) AF: 0.00 AC: 0 AN: 56152

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.43
PhyloP100		0.069

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: rs4919633; hg19: chr10-104159196;