2-37141309-T-C

Variant names:

• chr2-37141309-T-C
• rs2287350
• NM_001135651.3:c.389+244A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001135651.3(EIF2AK2):​c.389+244A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 152,082 control chromosomes in the GnomAD database, including 8,268 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8268 hom., cov: 32)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.837
• Publications: 5 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: Illumina, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

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.389+244A>G		intron	N/A	NP_001129123.1
	EIF2AK2	NM_002759.4		c.389+244A>G		intron	N/A	NP_002750.1
	EIF2AK2	NM_001135652.2		c.389+244A>G		intron	N/A	NP_001129124.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK2	ENST00000233057.9	TSL:2 MANE Select	c.389+244A>G		intron	N/A	ENSP00000233057.4
	EIF2AK2	ENST00000405334.5	TSL:1	c.389+244A>G		intron	N/A	ENSP00000385014.1
	EIF2AK2	ENST00000395127.6	TSL:5	c.389+244A>G		intron	N/A	ENSP00000378559.2

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46817 AN: 151964 Hom.: 8269 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.342

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.308 AC: 46823 AN: 152082 Hom.: 8268 Cov.: 32 AF XY: 0.310 AC XY: 23071 AN XY: 74326

African (AFR) AF: 0.135 AC: 5590 AN: 41504

American (AMR) AF: 0.328 AC: 5010 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1527 AN: 3472

East Asian (EAS) AF: 0.205 AC: 1061 AN: 5182

South Asian (SAS) AF: 0.235 AC: 1133 AN: 4822

European-Finnish (FIN) AF: 0.428 AC: 4521 AN: 10552

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26809 AN: 67958

Other (OTH) AF: 0.342 AC: 721 AN: 2108

Alfa AF: 0.366 Hom.: 40945

Bravo AF: 0.294

Asia WGS AF: 0.236 AC: 822 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.74
DANN	Benign	0.67
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2287350; hg19: chr2-37368452;