dbSNP rs9854688: IRAK2:p.Leu503Ile (chr3-10238781-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001570.4(IRAK2):c.1507C>A(p.Leu503Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,118 control chromosomes in the GnomAD database, including 586 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.037 ( 278 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 308 hom. )

Consequence

IRAK2
NM_001570.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.827

Publications

11 publications found

Variant links:

Genes affected

IRAK2 (HGNC:6113): (interleukin 1 receptor associated kinase 2) IRAK2 encodes the interleukin-1 receptor-associated kinase 2, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. IRAK2 is reported to participate in the IL1-induced upregulation of NF-kappaB. [provided by RefSeq, Jul 2008]

IRAK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022269785).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK2	NM_001570.4 link	c.1507C>A	p.Leu503Ile	missense_variant	Exon 12 of 13	ENST00000256458.5	NP_001561.3	O43187

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK2	ENST00000256458.5 link	c.1507C>A	p.Leu503Ile	missense_variant	Exon 12 of 13	1	NM_001570.4	ENSP00000256458.4		O43187

Frequencies

GnomAD3 genomes

AF:

0.0373

AC:

5668

AN:

152150

Hom.:

278

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0190

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00437

Gnomad OTH

AF:

0.0248

GnomAD2 exomes

AF:

0.0131

AC:

3296

AN:

251354

AF XY:

0.0113

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.0100

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00437

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00752

AC:

10996

AN:

1461852

Hom.:

308

Cov.:

AF XY:

0.00735

AC XY:

5347

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.124

AC:

4138

AN:

33474

American (AMR)

AF:

0.0105

AC:

469

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00429

AC:

112

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0127

AC:

1097

AN:

86258

European-Finnish (FIN)

AF:

0.00187

AC:

100

AN:

53420

Middle Eastern (MID)

AF:

0.0267

AC:

154

AN:

5768

European-Non Finnish (NFE)

AF:

0.00367

AC:

4083

AN:

1111984

Other (OTH)

AF:

0.0139

AC:

837

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

539

1078

1617

2156

2695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<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:

0.0373

AC:

5676

AN:

152266

Hom.:

278

Cov.:

AF XY:

0.0361

AC XY:

2691

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.119

AC:

4934

AN:

41514

American (AMR)

AF:

0.0189

AC:

290

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0122

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00437

AC:

297

AN:

68024

Other (OTH)

AF:

0.0241

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

269

538

806

1075

1344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0170

Hom.:

226

Bravo

AF:

0.0418

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.118

AC:

522

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.0155

AC:

1885

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00498

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.10

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

0.83

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.71

REVEL

Benign

0.033

Sift

Benign

0.15

Sift4G

Benign

0.28

Polyphen

0.39

Vest4

0.067

MPC

0.16

ClinPred

0.0037

GERP RS

3.3

Varity_R

0.078

gMVP

0.091

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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