rs9854688

Variant names:

• chr3-10238781-C-A
• rs9854688
• NM_001570.4:c.1507C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.827
• Publications: 11 publications found

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001570.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK2	NM_001570.4	MANE Select	c.1507C>A	p.Leu503Ile	missense	Exon 12 of 13	NP_001561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK2	ENST00000256458.5	TSL:1 MANE Select	c.1507C>A	p.Leu503Ile	missense	Exon 12 of 13	ENSP00000256458.4	O43187
	IRAK2	ENST00000971361.1		c.1600C>A	p.Leu534Ile	missense	Exon 13 of 14	ENSP00000641420.1
	IRAK2	ENST00000873197.1		c.1504C>A	p.Leu502Ile	missense	Exon 12 of 13	ENSP00000543256.1

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5668 AN: 152150 Hom.: 278 Cov.: 32

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

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.: 32 AF XY: 0.00735 AC XY: 5347 AN XY: 727230

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: 6 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

GnomAD4 genome AF: 0.0373 AC: 5676 AN: 152266 Hom.: 278 Cov.: 32 AF XY: 0.0361 AC XY: 2691 AN XY: 74446

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: 18 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4826

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10626

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00437 AC: 297 AN: 68024

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0170 Hom.: 226

Bravo AF: 0.0418

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.118 AC: 522

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.0155 AC: 1885

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00498

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.83
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.033
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.39	B
Vest4		0.067
MPC		0.16
ClinPred		0.0037	T
GERP RS		3.3
Varity_R		0.078
gMVP		0.091
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9854688; hg19: chr3-10280465;