2-37109262-G-T

Position:

• chr2-37109262-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135651.3(EIF2AK2):​c.1411C>A​(p.Leu471Ile) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L471L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK2 NM_001135651.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

Genes affected

EIF2AK2 (HGNC:9437): (eukaryotic translation initiation factor 2 alpha kinase 2) The protein encoded by this gene is a serine/threonine protein kinase that is activated by autophosphorylation after binding to dsRNA. The activated form of the encoded protein can phosphorylate translation initiation factor EIF2S1, which in turn inhibits protein synthesis. This protein is also activated by manganese ions and heparin. The encoded protein plays an important role in the innate immune response against multiple DNA and RNA viruses. [provided by RefSeq, Jul 2021]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102591455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK2	NM_001135651.3	c.1411C>A	p.Leu471Ile	missense_variant	15/17	ENST00000233057.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK2	ENST00000233057.9	c.1411C>A	p.Leu471Ile	missense_variant	15/17	2	NM_001135651.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with EIF2AK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 471 of the EIF2AK2 protein (p.Leu471Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.37
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.72	.;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.6	N;N;N
REVEL	Benign	0.049
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.25
MutPred		0.49		Gain of catalytic residue at L476 (P = 0.0835);Gain of catalytic residue at L476 (P = 0.0835);.;
MVP		0.41
MPC		0.29
ClinPred		0.40	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.28

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: rs967135397; hg19: chr2-37336405;