1-234607236-G-C

Position:

• chr1-234607236-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182972.3(IRF2BP2):​c.1665C>G​(p.Cys555Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF2BP2 NM_182972.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF2BP2	NM_182972.3	c.1665C>G	p.Cys555Trp	missense_variant	2/2	ENST00000366609.4	NP_892017.2
IRF2BP2	NM_001077397.1	c.1617C>G	p.Cys539Trp	missense_variant	2/2		NP_001070865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF2BP2	ENST00000366609.4	c.1665C>G	p.Cys555Trp	missense_variant	2/2	1	NM_182972.3	ENSP00000355568.3
IRF2BP2	ENST00000366610.7	c.1617C>G	p.Cys539Trp	missense_variant	2/2	1		ENSP00000355569.3
IRF2BP2	ENST00000491430.1	n.678C>G		non_coding_transcript_exon_variant	2/2	1
ENSG00000228830	ENST00000436039.1	n.229G>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.76		.;Loss of disorder (P = 0.1168);
MVP		0.98
MPC		0.58
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-234742982;