rs3770768

Variant names:

• chr2-37119008-G-A
• rs3770768
• NM_001135651.3:c.1248+951C>T

Variant summary

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

The NM_001135651.3(EIF2AK2):​c.1248+951C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 152,198 control chromosomes in the GnomAD database, including 860 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 0.097 (860 hom., cov: 32)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 7 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK2	NM_001135651.3	c.1248+951C>T		intron_variant	Intron 13 of 16	ENST00000233057.9	NP_001129123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK2	ENST00000233057.9	c.1248+951C>T		intron_variant	Intron 13 of 16	2	NM_001135651.3	ENSP00000233057.4

Frequencies

GnomAD3 genomes AF: 0.0971 AC: 14767 AN: 152080 Hom.: 860 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.0955

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.0971 AC: 14771 AN: 152198 Hom.: 860 Cov.: 32 AF XY: 0.0984 AC XY: 7320 AN XY: 74398

African (AFR) AF: 0.0612 AC: 2543 AN: 41524

American (AMR) AF: 0.0578 AC: 883 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3470

East Asian (EAS) AF: 0.00618 AC: 32 AN: 5182

South Asian (SAS) AF: 0.139 AC: 669 AN: 4824

European-Finnish (FIN) AF: 0.151 AC: 1601 AN: 10586

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.123 AC: 8363 AN: 68010

Other (OTH) AF: 0.101 AC: 214 AN: 2110

Alfa AF: 0.113 Hom.: 1782

Bravo AF: 0.0856

Asia WGS AF: 0.0510 AC: 178 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.7
DANN	Benign	0.61
PhyloP100		1.5
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: rs3770768; hg19: chr2-37346151;