dbSNP rs708035: IRAK2:p.Asp431Glu (chr3-10234479-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001570.4(IRAK2):c.1293T>A(p.Asp431Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,613,494 control chromosomes in the GnomAD database, including 375,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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 Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.71 ( 38440 hom., cov: 32)

Exomes 𝑓: 0.67 ( 336754 hom. )

Consequence

IRAK2
NM_001570.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.297

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.7530127E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK2	NM_001570.4 link	c.1293T>A	p.Asp431Glu	missense_variant	Exon 11 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.1293T>A	p.Asp431Glu	missense_variant	Exon 11 of 13	1	NM_001570.4	ENSP00000256458.4		O43187

Frequencies

GnomAD3 genomes

AF:

0.706

AC:

107267

AN:

151980

Hom.:

38404

Cov.:

show subpopulations

Gnomad AFR

AF:

0.769

Gnomad AMI

AF:

0.671

Gnomad AMR

AF:

0.760

Gnomad ASJ

AF:

0.688

Gnomad EAS

AF:

0.993

Gnomad SAS

AF:

0.891

Gnomad FIN

AF:

0.631

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.633

Gnomad OTH

AF:

0.699

GnomAD3 exomes

AF:

0.729

AC:

183045

AN:

251192

Hom.:

68803

AF XY:

0.729

AC XY:

99035

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.772

Gnomad AMR exome

AF:

0.828

Gnomad ASJ exome

AF:

0.687

Gnomad EAS exome

AF:

0.996

Gnomad SAS exome

AF:

0.878

Gnomad FIN exome

AF:

0.623

Gnomad NFE exome

AF:

0.635

Gnomad OTH exome

AF:

0.692

GnomAD4 exome

AF:

0.673

AC:

983485

AN:

1461396

Hom.:

336754

Cov.:

AF XY:

0.678

AC XY:

492837

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.773

Gnomad4 AMR exome

AF:

0.820

Gnomad4 ASJ exome

AF:

0.684

Gnomad4 EAS exome

AF:

0.993

Gnomad4 SAS exome

AF:

0.875

Gnomad4 FIN exome

AF:

0.628

Gnomad4 NFE exome

AF:

0.638

Gnomad4 OTH exome

AF:

0.689

GnomAD4 genome

AF:

0.706

AC:

107359

AN:

152098

Hom.:

38440

Cov.:

AF XY:

0.712

AC XY:

52973

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.769

Gnomad4 AMR

AF:

0.760

Gnomad4 ASJ

AF:

0.688

Gnomad4 EAS

AF:

0.993

Gnomad4 SAS

AF:

0.890

Gnomad4 FIN

AF:

0.631

Gnomad4 NFE

AF:

0.633

Gnomad4 OTH

AF:

0.697

Alfa

AF:

0.657

Hom.:

25167

Bravo

AF:

0.717

TwinsUK

AF:

0.637

AC:

2361

ALSPAC

AF:

0.649

AC:

2501

ESP6500AA

AF:

0.764

AC:

3367

ESP6500EA

AF:

0.633

AC:

5448

ExAC

AF:

0.726

AC:

88143

Asia WGS

AF:

0.913

AC:

3174

AN:

3478

EpiCase

AF:

0.641

EpiControl

AF:

0.634

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.058

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.075

MetaRNN

Benign

5.8e-7

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.6

PrimateAI

Benign

0.47

PROVEAN

Benign

2.4

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.015

MutPred

0.084

Gain of glycosylation at P433 (P = 0.1188);

MPC

0.13

ClinPred

0.0014

GERP RS

-1.1

Varity_R

0.042

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over