rs2307483

Variant names:

• chr2-37138655-A-G
• rs2307483
• NM_001135651.3:c.517-70T>C

Variant summary

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

The NM_001135651.3(EIF2AK2):​c.517-70T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 1,291,672 control chromosomes in the GnomAD database, including 5,237 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 0.10 (988 hom., cov: 32)
  • Exomes 𝑓: 0.083 (4249 hom.)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• Publications: 3 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK2	NM_001135651.3	MANE Select	c.517-70T>C		intron	N/A	NP_001129123.1
	EIF2AK2	NM_002759.4		c.517-70T>C		intron	N/A	NP_002750.1
	EIF2AK2	NM_001135652.2		c.517-70T>C		intron	N/A	NP_001129124.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK2	ENST00000233057.9	TSL:2 MANE Select	c.517-70T>C		intron	N/A	ENSP00000233057.4
	EIF2AK2	ENST00000405334.5	TSL:1	c.517-70T>C		intron	N/A	ENSP00000385014.1
	EIF2AK2	ENST00000395127.6	TSL:5	c.517-70T>C		intron	N/A	ENSP00000378559.2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15293 AN: 152146 Hom.: 983 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0650

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0891

Gnomad FIN AF: 0.0559

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.0963

GnomAD4 exome AF: 0.0825 AC: 94042 AN: 1139408 Hom.: 4249 AF XY: 0.0828 AC XY: 47911 AN XY: 578572

African (AFR) AF: 0.191 AC: 4957 AN: 25976

American (AMR) AF: 0.0505 AC: 1889 AN: 37394

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2508 AN: 22874

East Asian (EAS) AF: 0.000602 AC: 22 AN: 36566

South Asian (SAS) AF: 0.0990 AC: 7374 AN: 74488

European-Finnish (FIN) AF: 0.0593 AC: 3090 AN: 52148

Middle Eastern (MID) AF: 0.101 AC: 517 AN: 5114

European-Non Finnish (NFE) AF: 0.0828 AC: 69216 AN: 835486

Other (OTH) AF: 0.0905 AC: 4469 AN: 49362

GnomAD4 genome AF: 0.101 AC: 15333 AN: 152264 Hom.: 988 Cov.: 32 AF XY: 0.0984 AC XY: 7324 AN XY: 74452

African (AFR) AF: 0.179 AC: 7451 AN: 41522

American (AMR) AF: 0.0649 AC: 993 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.0896 AC: 433 AN: 4832

European-Finnish (FIN) AF: 0.0559 AC: 594 AN: 10624

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0761 AC: 5178 AN: 68016

Other (OTH) AF: 0.0948 AC: 200 AN: 2110

Alfa AF: 0.0937 Hom.: 305

Bravo AF: 0.104

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.3
DANN	Benign	0.54
PhyloP100		0.11
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: rs2307483; hg19: chr2-37365798;