Genetic Variant IRF2BP2:p.His63Gln (chr1-234609306-G-C) – 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.189C>G(p.His63Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

IRF2BP2
NM_182972.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.72

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.189C>G	p.His63Gln	missense_variant	Exon 1 of 2	ENST00000366609.4	NP_892017.2	Q7Z5L9-1
IRF2BP2	NM_001077397.1 link	c.189C>G	p.His63Gln	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.189C>G	p.His63Gln	missense_variant	Exon 1 of 2	1	NM_182972.3	ENSP00000355568.3	Q7Z5L9-1
IRF2BP2	ENST00000366610.8 link	c.189C>G	p.His63Gln	missense_variant	Exon 1 of 2	1		ENSP00000355569.3	Q7Z5L9-2
LINC00184	ENST00000796406.1 link	n.12G>C		non_coding_transcript_exon_variant	Exon 1 of 4
ENSG00000228830	ENST00000436039.1 link	n.631-115G>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.43e-7

AC:

AN:

1345888

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

664450

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27264

American (AMR)

AF:

0.00

AC:

AN:

29508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23430

East Asian (EAS)

AF:

0.00

AC:

AN:

29322

South Asian (SAS)

AF:

0.0000134

AC:

AN:

74512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4188

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1055808

Other (OTH)

AF:

0.00

AC:

AN:

55354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.00021

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.20

.;T

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.2

L;L

PhyloP100

2.7

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Benign

0.29

Sift

Benign

0.035

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.52

MutPred

0.39

Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);

MVP

0.88

MPC

2.3

ClinPred

0.99

GERP RS

2.6

PromoterAI

0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.57

Mutation Taster

=31/69

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

Computational scores

Splicing

Publications

Other links and lift over