2-37146107-T-C

Variant names:

• chr2-37146107-T-C
• rs2373114
• NM_001135651.3:c.240+746A>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.240+746A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 152,052 control chromosomes in the GnomAD database, including 55,551 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 0.84 (55551 hom., cov: 30)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.240+746A>G		intron	N/A	NP_001129123.1	P19525-1
	EIF2AK2	NM_002759.4		c.240+746A>G		intron	N/A	NP_002750.1	P19525-1
	EIF2AK2	NM_001135652.2		c.240+746A>G		intron	N/A	NP_001129124.1	P19525-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK2	ENST00000233057.9	TSL:2 MANE Select	c.240+746A>G		intron	N/A	ENSP00000233057.4	P19525-1
	EIF2AK2	ENST00000405334.5	TSL:1	c.240+746A>G		intron	N/A	ENSP00000385014.1	P19525-2
	EIF2AK2	ENST00000395127.6	TSL:5	c.240+746A>G		intron	N/A	ENSP00000378559.2	P19525-1

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128230 AN: 151934 Hom.: 55535 Cov.: 30

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.913

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.944

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.923

Gnomad OTH AF: 0.868

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

GnomAD4 genome AF: 0.844 AC: 128295 AN: 152052 Hom.: 55551 Cov.: 30 AF XY: 0.848 AC XY: 63072 AN XY: 74336

African (AFR) AF: 0.628 AC: 25990 AN: 41384

American (AMR) AF: 0.913 AC: 13959 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3109 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5164 AN: 5174

South Asian (SAS) AF: 0.909 AC: 4386 AN: 4824

European-Finnish (FIN) AF: 0.944 AC: 9995 AN: 10588

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.923 AC: 62764 AN: 68014

Other (OTH) AF: 0.870 AC: 1834 AN: 2108

Alfa AF: 0.875 Hom.: 9869

Bravo AF: 0.832

Asia WGS AF: 0.939 AC: 3267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.0
DANN	Benign	0.72
PhyloP100		0.31
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: rs2373114; hg19: chr2-37373250;