dbSNP rs3844283: IRAK2:p.Leu392Val (chr3-10222796-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001570.4(IRAK2):c.1174C>G(p.Leu392Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,594 control chromosomes in the GnomAD database, including 131,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9768 hom., cov: 32)

Exomes 𝑓: 0.40 ( 121240 hom. )

Consequence

IRAK2
NM_001570.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.68

Publications

45 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045402646).

BP6

Variant 3-10222796-C-G is Benign according to our data. Variant chr3-10222796-C-G is described in ClinVar as Benign. ClinVar VariationId is 1232409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK2	NM_001570.4 link	c.1174C>G	p.Leu392Val	missense_variant	Exon 9 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.1174C>G	p.Leu392Val	missense_variant	Exon 9 of 13	1	NM_001570.4	ENSP00000256458.4		O43187

Frequencies

GnomAD3 genomes

AF:

0.348

AC:

52860

AN:

151938

Hom.:

9765

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.438

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.363

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.303

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.363

GnomAD2 exomes

AF:

0.368

AC:

92496

AN:

251450

AF XY:

0.368

show subpopulations

Gnomad AFR exome

AF:

0.229

Gnomad AMR exome

AF:

0.470

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.344

Gnomad NFE exome

AF:

0.413

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.401

AC:

586025

AN:

1461538

Hom.:

121240

Cov.:

AF XY:

0.399

AC XY:

289765

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.223

AC:

7470

AN:

33474

American (AMR)

AF:

0.469

AC:

20978

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

9451

AN:

26134

East Asian (EAS)

AF:

0.108

AC:

4277

AN:

39700

South Asian (SAS)

AF:

0.323

AC:

27846

AN:

86254

European-Finnish (FIN)

AF:

0.355

AC:

18971

AN:

53410

Middle Eastern (MID)

AF:

0.334

AC:

1929

AN:

5768

European-Non Finnish (NFE)

AF:

0.425

AC:

472304

AN:

1111684

Other (OTH)

AF:

0.378

AC:

22799

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

17695

35390

53086

70781

88476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14270

28540

42810

57080

71350

<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:

0.348

AC:

52870

AN:

152056

Hom.:

9768

Cov.:

AF XY:

0.345

AC XY:

25612

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.235

AC:

9737

AN:

41506

American (AMR)

AF:

0.428

AC:

6529

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

1260

AN:

3468

East Asian (EAS)

AF:

0.126

AC:

654

AN:

5178

South Asian (SAS)

AF:

0.303

AC:

1460

AN:

4818

European-Finnish (FIN)

AF:

0.351

AC:

3714

AN:

10568

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.416

AC:

28285

AN:

67936

Other (OTH)

AF:

0.359

AC:

757

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1740

3480

5219

6959

8699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.396

Hom.:

9443

Bravo

AF:

0.350

TwinsUK

AF:

0.417

AC:

1546

ALSPAC

AF:

0.430

AC:

1659

ESP6500AA

AF:

0.233

AC:

1026

ESP6500EA

AF:

0.419

AC:

3605

ExAC

AF:

0.361

AC:

43846

Asia WGS

AF:

0.237

AC:

830

AN:

3478

EpiCase

AF:

0.419

EpiControl

AF:

0.404

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26250868) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

PhyloP100

1.7

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.25

MPC

0.60

ClinPred

0.020

GERP RS

5.1

Varity_R

0.62

gMVP

0.38

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over