rs3844283

Positions:

• chr3-10222796-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.35 (9768 hom., cov: 32)
  • Exomes 𝑓: 0.40 (121240 hom.)
• Consequence: IRAK2 NM_001570.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.68

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 -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 id 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/exons	MANE	Protein	UniProt
IRAK2	NM_001570.4	c.1174C>G	p.Leu392Val	missense_variant	9/13	ENST00000256458.5	NP_001561.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK2	ENST00000256458.5	c.1174C>G	p.Leu392Val	missense_variant	9/13	1	NM_001570.4	ENSP00000256458	P1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52860 AN: 151938 Hom.: 9765 Cov.: 32

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

GnomAD3 exomes AF: 0.368 AC: 92496 AN: 251450 Hom.: 18278 AF XY: 0.368 AC XY: 49986 AN XY: 135900

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 SAS exome AF: 0.323

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.: 43 AF XY: 0.399 AC XY: 289765 AN XY: 727102

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.323

Gnomad4 FIN exome AF: 0.355

Gnomad4 NFE exome AF: 0.425

Gnomad4 OTH exome AF: 0.378

GnomAD4 genome AF: 0.348 AC: 52870 AN: 152056 Hom.: 9768 Cov.: 32 AF XY: 0.345 AC XY: 25612 AN XY: 74318

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.363

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.416

Gnomad4 OTH AF: 0.359

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	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	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.000020	P
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.25
MPC		0.60
ClinPred		0.020	T
GERP RS		5.1
Varity_R		0.62
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs3844283; hg19: chr3-10264480; COSMIC: COSV56529718;