2-37109287-C-G

Variant names:

• chr2-37109287-C-G
• rs774118494
• NM_001135651.3:c.1386G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001135651.3(EIF2AK2):​c.1386G>C​(p.Ser462Ser) variant causes a synonymous 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S462S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK2 NM_001135651.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.514
• Publications: 0 publications found

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]

EIF2AK2 Gene-Disease associations (from GenCC):

• leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• early-onset generalized limb-onset dystonia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dystonia 33

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-0.514 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135651.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK2	NM_001135651.3	MANE Select	c.1386G>C	p.Ser462Ser	synonymous	Exon 15 of 17	NP_001129123.1	P19525-1
	EIF2AK2	NM_002759.4		c.1386G>C	p.Ser462Ser	synonymous	Exon 15 of 17	NP_002750.1	P19525-1
	EIF2AK2	NM_001135652.2		c.1263G>C	p.Ser421Ser	synonymous	Exon 12 of 14	NP_001129124.1	P19525-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK2	ENST00000233057.9	TSL:2 MANE Select	c.1386G>C	p.Ser462Ser	synonymous	Exon 15 of 17	ENSP00000233057.4	P19525-1
	EIF2AK2	ENST00000405334.5	TSL:1	c.1263G>C	p.Ser421Ser	synonymous	Exon 12 of 14	ENSP00000385014.1	P19525-2
	EIF2AK2	ENST00000395127.6	TSL:5	c.1386G>C	p.Ser462Ser	synonymous	Exon 15 of 17	ENSP00000378559.2	P19525-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs774118494; hg19: chr2-37336430;