rs4648174

Variant names:

• chr2-37141907-T-C
• rs4648174
• NM_001135651.3:c.241-206A>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.241-206A>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 152,080 control chromosomes in the GnomAD database, including 8,265 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 (8265 hom., cov: 32)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 6 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK2	NM_001135651.3	c.241-206A>G		intron_variant	Intron 4 of 16	ENST00000233057.9	NP_001129123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK2	ENST00000233057.9	c.241-206A>G		intron_variant	Intron 4 of 16	2	NM_001135651.3	ENSP00000233057.4

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46811 AN: 151962 Hom.: 8266 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.343

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

GnomAD4 genome AF: 0.308 AC: 46817 AN: 152080 Hom.: 8265 Cov.: 32 AF XY: 0.310 AC XY: 23068 AN XY: 74324

African (AFR) AF: 0.134 AC: 5578 AN: 41502

American (AMR) AF: 0.328 AC: 5008 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1540 AN: 3472

East Asian (EAS) AF: 0.206 AC: 1065 AN: 5172

South Asian (SAS) AF: 0.234 AC: 1127 AN: 4814

European-Finnish (FIN) AF: 0.428 AC: 4525 AN: 10566

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

European-Non Finnish (NFE) AF: 0.394 AC: 26801 AN: 67968

Other (OTH) AF: 0.342 AC: 723 AN: 2112

Alfa AF: 0.331 Hom.: 1171

Bravo AF: 0.294

Asia WGS AF: 0.233 AC: 811 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.46
PhyloP100		-0.53
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: rs4648174; hg19: chr2-37369050;