rs1572996700

Variant names:

• chr2-37109291-G-C
• rs1572996700
• NM_001135651.3:c.1382C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001135651.3(EIF2AK2):​c.1382C>G​(p.Ser461Cys) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK2 NM_001135651.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: -0.385

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-37109291-G-C is Pathogenic according to our data. Variant chr2-37109291-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 818200.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr2-37109291-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.24691221). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK2	NM_001135651.3	c.1382C>G	p.Ser461Cys	missense_variant	Exon 15 of 17	ENST00000233057.9	NP_001129123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK2	ENST00000233057.9	c.1382C>G	p.Ser461Cys	missense_variant	Exon 15 of 17	2	NM_001135651.3	ENSP00000233057.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome Pathogenic:2 Uncertain:1

Jun 08, 2021

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EIF2AK2 c.1382C>G (p.Ser461Cys) variant is a missense variant that is located in the protein-kinase domain of the EIF2AK2 protein (Mao et al. 2020). The p.Ser461Cys variant has been reported in a de novo state in one individual with leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (Mao et al. 2020). The p.Ser461Cys variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database in a region of good sequence coverage, which suggests the variant is rare. Functional studies in patient fibroblasts for the p.Ser461Cys variant demonstrated impaired kinase activity with consistent reduction in p-EIF2S1 levels and decrease in ATF4 levels, a downstream target of p-EIF2S1 (Mao et al. 2020). Based on the collective evidence and identification of this variant in a de novo state, the p.Ser461Cys variant is classified as likely pathogenic for leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome. -

Dec 18, 2020

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a variant of uncertain significance for Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, autosomal dominant The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); de novo variant (PS2 downgraded to moderate); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting). -

Feb 10, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leukoencephalopathy;C0557874:Global developmental delay;C1836830:Developmental regression Uncertain:1

Mar 09, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.1382C>G (p.Ser461Cys) variant in EIF2AK2 was identified by our study in 1 individual with developmental regression, leukoencephalopathy, and global developmental delay. Trio exome analysis showed this variant to be de novo with confirmed paternity and maternity. The c.1382C>G (p.Ser461Cys) variant in EIF2AK2 has not been previously reported in individuals with developmental regression, leukoencephalopathy, and global developmental delay and this variant was absent from large population studies. The EIF2AK2 gene has no established gene-disease association. However, this gene has a role in the EIF2B pathway, which has been associated with vanishing white matter leukoencephalopathies. Unpublished cohort data has identified other unrelated patients with similar neurologic phenotypes and suggest that de novo missense variants are implicated in disease. Functional studies demonstrate this variant impairs kinase activity of EIF2AK2 (publication pending). It is of note that computational prediction tools, including splice predictors, suggest that this variant may not impact the protein. Additionally, the serine (Ser) at position 461 is not highly conserved in mammals and evolutionary distant species, and 2 mammals (dolphins and killer whales) carry a cystine (Cys), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the Ser461Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T;T;.
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.11
Sift	Benign	0.044	D;D;D
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.18
MutPred		0.44		Loss of disorder (P = 4e-04);Loss of disorder (P = 4e-04);.;
MVP		0.87
MPC		0.31
ClinPred		0.43	T
GERP RS		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1572996700; hg19: chr2-37336434;