1-234607143-GTCTC-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_182972.3(IRF2BP2):c.1754_1757del(p.Arg585ThrfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: IRF2BP2 NM_182972.3 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.97

Genes affected

IRF2BP2 (HGNC:21729): (interferon regulatory factor 2 binding protein 2) This gene encodes an interferon regulatory factor-2 (IRF2) binding protein that interacts with the C-terminal transcriptional repression domain of IRF2. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 588 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF2BP2	NM_182972.3	c.1754_1757del	p.Arg585ThrfsTer12	frameshift_variant	2/2	ENST00000366609.4
IRF2BP2	NM_001077397.1	c.1706_1709del	p.Arg569ThrfsTer12	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF2BP2	ENST00000366609.4	c.1754_1757del	p.Arg585ThrfsTer12	frameshift_variant	2/2	1	NM_182972.3	P3
IRF2BP2	ENST00000366610.7	c.1706_1709del	p.Arg569ThrfsTer12	frameshift_variant	2/2	1		A1
	ENST00000436039.1	n.142_145del		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453958 Hom.: 0 AF XY: 0.00000277 AC XY: 2 AN XY: 721878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Varicella, severe recurrent Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP)- HUVH-VHIR, Vall d'Hebron University Hospital

-

This variant is a deletion of 4 nucleotides in the IRF2BP2 gene located at the end of exon 2 (c.1754_1757del). This variant is very close to the end of the protein, affecting the residue 585 out of 587, causing a frameshift, and adding an additional stretch of amino acids beyond the original STOP codon (p.Arg585Thrfs*12). This makes the possible mutant protein longer than the wild type (595 vs 587 amino acids respectively). This variant was not reported in the gnomAD database. We found this variant in a patient with severe and recurrent varicella zoster virus (VZV) infection and significant VZV vaccine side-effects. The variant was inherited from his apparently asymptomatic father. The available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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: rs764480409; hg19: chr1-234742889;