3-10222648-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001570.4(IRAK2):c.1026G>T(p.Leu342Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRAK2 NM_001570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK2	NM_001570.4	c.1026G>T	p.Leu342Phe	missense_variant	9/13	ENST00000256458.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK2	ENST00000256458.5	c.1026G>T	p.Leu342Phe	missense_variant	9/13	1	NM_001570.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.1026G>T (p.L342F) alteration is located in exon 9 (coding exon 9) of the IRAK2 gene. This alteration results from a G to T substitution at nucleotide position 1026, causing the leucine (L) at amino acid position 342 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.39
Sift	Benign	0.099	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.90		Loss of ubiquitination at K337 (P = 0.1037);
MVP		0.85
MPC		0.62
ClinPred		0.97	D
GERP RS		2.4
Varity_R		0.38
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10264332;