Genetic Variant IRF2BP2:p.Glu44Lys (chr1-234609365-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_182972.3(IRF2BP2):c.130G>A(p.Glu44Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IRF2BP2
NM_182972.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.47

Publications

0 publications found

Variant links:

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 links:

LINC00184 (HGNC:37192): (long intergenic non-protein coding RNA 184)

LINC00184 links:

ENSG00000228830 (HGNC:):

ENSG00000228830 links:

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ACMG classification

Classification was made for transcript

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 link	c.130G>A	p.Glu44Lys	missense_variant	Exon 1 of 2	ENST00000366609.4	NP_892017.2	Q7Z5L9-1
IRF2BP2	NM_001077397.1 link	c.130G>A	p.Glu44Lys	missense_variant	Exon 1 of 2		NP_001070865.1	Q7Z5L9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRF2BP2	ENST00000366609.4 link	c.130G>A	p.Glu44Lys	missense_variant	Exon 1 of 2	1	NM_182972.3	ENSP00000355568.3	Q7Z5L9-1
IRF2BP2	ENST00000366610.8 link	c.130G>A	p.Glu44Lys	missense_variant	Exon 1 of 2	1		ENSP00000355569.3	Q7Z5L9-2
LINC00184	ENST00000796406.1 link	n.71C>T		non_coding_transcript_exon_variant	Exon 1 of 4
ENSG00000228830	ENST00000436039.1 link	n.631-56C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1400204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694872

African (AFR)

AF:

0.00

AC:

AN:

28814

American (AMR)

AF:

0.00

AC:

AN:

37982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24544

East Asian (EAS)

AF:

0.00

AC:

AN:

32980

South Asian (SAS)

AF:

0.00

AC:

AN:

79640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5138

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083898

Other (OTH)

AF:

0.00

AC:

AN:

57658

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 44 of the IRF2BP2 protein (p.Glu44Lys). 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. 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

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;T

Eigen

Benign

0.13

Eigen_PC

Benign

-0.045

FATHMM_MKL

Uncertain

0.78

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.61

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.5

L;L

PhyloP100

6.5

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.59

MutPred

0.59

Gain of ubiquitination at E44 (P = 0.0203);Gain of ubiquitination at E44 (P = 0.0203);

MVP

0.63

MPC

2.4

ClinPred

0.99

GERP RS

1.8

PromoterAI

-0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.69

gMVP

0.79

Mutation Taster

=32/68

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over