Genetic Variant IRF2:p.Gly248Gly (chr4-184389064-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_002199.4(IRF2):c.744G>A(p.Gly248Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,611,808 control chromosomes in the GnomAD database, including 129,879 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.39 ( 11585 hom., cov: 32)

Exomes 𝑓: 0.40 ( 118294 hom. )

Consequence

IRF2
NM_002199.4 splice_region, synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.24

Publications

22 publications found

Variant links:

Genes affected

IRF2 (HGNC:6117): (interferon regulatory factor 2) IRF2 encodes interferon regulatory factor 2, a member of the interferon regulatory transcription factor (IRF) family. IRF2 competitively inhibits the IRF1-mediated transcriptional activation of interferons alpha and beta, and presumably other genes that employ IRF1 for transcription activation. However, IRF2 also functions as a transcriptional activator of histone H4. [provided by RefSeq, Jul 2008]

IRF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.013).

BP7

Synonymous conserved (PhyloP=-1.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF2	NM_002199.4 link	c.744G>A	p.Gly248Gly	splice_region_variant, synonymous_variant	Exon 9 of 9	ENST00000393593.8	NP_002190.2	P14316-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF2	ENST00000393593.8 link	c.744G>A	p.Gly248Gly	splice_region_variant, synonymous_variant	Exon 9 of 9	1	NM_002199.4	ENSP00000377218.3		P14316-1

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58841

AN:

151940

Hom.:

11579

Cov.:

show subpopulations

Gnomad AFR

AF:

0.344

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.473

Gnomad ASJ

AF:

0.387

Gnomad EAS

AF:

0.410

Gnomad SAS

AF:

0.508

Gnomad FIN

AF:

0.364

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.389

Gnomad OTH

AF:

0.410

GnomAD2 exomes

AF:

0.427

AC:

106260

AN:

248924

AF XY:

0.426

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.582

Gnomad ASJ exome

AF:

0.391

Gnomad EAS exome

AF:

0.408

Gnomad FIN exome

AF:

0.371

Gnomad NFE exome

AF:

0.386

Gnomad OTH exome

AF:

0.407

GnomAD4 exome

AF:

0.399

AC:

582891

AN:

1459750

Hom.:

118294

Cov.:

AF XY:

0.402

AC XY:

291785

AN XY:

726288

show subpopulations

African (AFR)

AF:

0.340

AC:

11368

AN:

33438

American (AMR)

AF:

0.564

AC:

25190

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.393

AC:

10258

AN:

26120

East Asian (EAS)

AF:

0.388

AC:

15405

AN:

39690

South Asian (SAS)

AF:

0.511

AC:

44023

AN:

86204

European-Finnish (FIN)

AF:

0.370

AC:

19758

AN:

53412

Middle Eastern (MID)

AF:

0.371

AC:

2138

AN:

5762

European-Non Finnish (NFE)

AF:

0.388

AC:

430527

AN:

1110106

Other (OTH)

AF:

0.402

AC:

24224

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

17313

34626

51940

69253

86566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13566

27132

40698

54264

67830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.387

AC:

58879

AN:

152058

Hom.:

11585

Cov.:

AF XY:

0.390

AC XY:

28977

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.344

AC:

14257

AN:

41464

American (AMR)

AF:

0.474

AC:

7239

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.387

AC:

1341

AN:

3468

East Asian (EAS)

AF:

0.410

AC:

2123

AN:

5176

South Asian (SAS)

AF:

0.507

AC:

2441

AN:

4812

European-Finnish (FIN)

AF:

0.364

AC:

3847

AN:

10564

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.389

AC:

26413

AN:

67986

Other (OTH)

AF:

0.412

AC:

866

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1864

3729

5593

7458

9322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

578

1156

1734

2312

2890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.386

Hom.:

14318

Bravo

AF:

0.393

Asia WGS

AF:

0.492

AC:

1714

AN:

3478

EpiCase

AF:

0.380

EpiControl

AF:

0.379

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.3

(source)

DANN

Benign

0.55

PhyloP100

-1.2

Mutation Taster

=93/7

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over