rs4648212

Variant names:

• chr2-37125868-C-T
• rs4648212
• NM_001135651.3:c.908+421G>A

Variant summary

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

The NM_001135651.3(EIF2AK2):​c.908+421G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 152,268 control chromosomes in the GnomAD database, including 147 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 0.037 (147 hom., cov: 32)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.798
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK2	NM_001135651.3	c.908+421G>A		intron_variant	Intron 11 of 16	ENST00000233057.9	NP_001129123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK2	ENST00000233057.9	c.908+421G>A		intron_variant	Intron 11 of 16	2	NM_001135651.3	ENSP00000233057.4

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5687 AN: 152150 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0444

Gnomad FIN AF: 0.0404

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0534

Gnomad OTH AF: 0.0488

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

GnomAD4 genome AF: 0.0374 AC: 5688 AN: 152268 Hom.: 147 Cov.: 32 AF XY: 0.0375 AC XY: 2793 AN XY: 74450

African (AFR) AF: 0.0107 AC: 443 AN: 41560

American (AMR) AF: 0.0371 AC: 568 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0740 AC: 257 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0450 AC: 217 AN: 4820

European-Finnish (FIN) AF: 0.0404 AC: 428 AN: 10604

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0534 AC: 3633 AN: 68006

Other (OTH) AF: 0.0483 AC: 102 AN: 2112

Alfa AF: 0.0402 Hom.: 15

Bravo AF: 0.0356

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.89
DANN	Benign	0.47
PhyloP100		-0.80
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: rs4648212; hg19: chr2-37353011;