rs9854688

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 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 0.037 (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

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

Verdict is Benign. Variant got -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	c.1507C>A	p.Leu503Ile	missense_variant	Exon 12 of 13	ENST00000256458.5	NP_001561.3

Ensembl

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

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

GnomAD3 exomes AF: 0.0131 AC: 3296 AN: 251354 Hom.: 128 AF XY: 0.0113 AC XY: 1538 AN XY: 135860

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 SAS exome AF: 0.0117

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

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00367

Gnomad4 OTH exome AF: 0.0139

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

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00437

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0115 Hom.: 97

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 v4.3

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
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

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

LitVar

Other links and lift over

dbSNP: rs9854688; hg19: chr3-10280465;