rs708035

chr3-10234479-T-Achr3-10234479-T-Cchr3-10234479-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.71 (38440 hom., cov: 32)
  • Exomes 𝑓: 0.67 (336754 hom.)
• Consequence: IRAK2 NM_001570.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.297

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=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/exons	MANE	UniProt
IRAK2	NM_001570.4	c.1293T>A	p.Asp431Glu	missense_variant	11/13	ENST00000256458.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK2	ENST00000256458.5	c.1293T>A	p.Asp431Glu	missense_variant	11/13	1	NM_001570.4	P1

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107267 AN: 151980 Hom.: 38404 Cov.: 32

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

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.: 47 AF XY: 0.678 AC XY: 492837 AN XY: 726980

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.: 32 AF XY: 0.712 AC XY: 52973 AN XY: 74358

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	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	11
Dann	Benign	0.61
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.075	T
MetaRNN	Benign	5.8e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.084		Gain of glycosylation at P433 (P = 0.1188);
MPC		0.13
ClinPred		0.0014	T
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

Other links and lift over

dbSNP: rs708035; hg19: chr3-10276163; COSMIC: COSV56532113;