1-234607229-C-G

Variant names:

• chr1-234607229-C-G
• rs747870654
• NM_182972.3:c.1672G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182972.3(IRF2BP2):​c.1672G>C​(p.Val558Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V558E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IRF2BP2 NM_182972.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04
• Publications: 0 publications found

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]

IRF2BP2 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 14

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000228830 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF2BP2	NM_182972.3	c.1672G>C	p.Val558Leu	missense_variant	Exon 2 of 2	ENST00000366609.4	NP_892017.2
IRF2BP2	NM_001077397.1	c.1624G>C	p.Val542Leu	missense_variant	Exon 2 of 2		NP_001070865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF2BP2	ENST00000366609.4	c.1672G>C	p.Val558Leu	missense_variant	Exon 2 of 2	1	NM_182972.3	ENSP00000355568.3
IRF2BP2	ENST00000366610.8	c.1624G>C	p.Val542Leu	missense_variant	Exon 2 of 2	1		ENSP00000355569.3
ENSG00000228830	ENST00000436039.1	n.222C>G		non_coding_transcript_exon_variant	Exon 1 of 2	3
IRF2BP2	ENST00000491430.1	n.*2G>C		downstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 558 of the IRF2BP2 protein (p.Val558Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IRF2BP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2104574). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0071	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.2	.;L
PhyloP100		6.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.31		.;Gain of ubiquitination at K554 (P = 0.1679);
MVP		0.75
MPC		0.39
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.56
gMVP		0.50
Mutation Taster		=58/42	polymorphism

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: rs747870654; hg19: chr1-234742975;