chr2-37135412-T-G

Variant names:

• chr2-37135412-T-G
• rs2307479
• NM_001135651.3:c.785+72A>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.785+72A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,280,648 control chromosomes in the GnomAD database, including 1,243 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 0.057 (397 hom., cov: 32)
  • Exomes 𝑓: 0.034 (846 hom.)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 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.785+72A>C		intron	N/A	NP_001129123.1	P19525-1
	EIF2AK2	NM_002759.4		c.785+72A>C		intron	N/A	NP_002750.1	P19525-1
	EIF2AK2	NM_001135652.2		c.785+72A>C		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.785+72A>C		intron	N/A	ENSP00000233057.4	P19525-1
	EIF2AK2	ENST00000405334.5	TSL:1	c.785+72A>C		intron	N/A	ENSP00000385014.1	P19525-2
	EIF2AK2	ENST00000395127.6	TSL:5	c.785+72A>C		intron	N/A	ENSP00000378559.2	P19525-1

Frequencies

GnomAD3 genomes AF: 0.0574 AC: 8729 AN: 152134 Hom.: 394 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0454

GnomAD4 exome AF: 0.0339 AC: 38205 AN: 1128396 Hom.: 846 AF XY: 0.0343 AC XY: 19583 AN XY: 571526

African (AFR) AF: 0.127 AC: 3162 AN: 24980

American (AMR) AF: 0.0256 AC: 811 AN: 31670

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 672 AN: 21128

East Asian (EAS) AF: 0.000509 AC: 19 AN: 37320

South Asian (SAS) AF: 0.0404 AC: 2865 AN: 70834

European-Finnish (FIN) AF: 0.0244 AC: 1253 AN: 51346

Middle Eastern (MID) AF: 0.0433 AC: 216 AN: 4994

European-Non Finnish (NFE) AF: 0.0328 AC: 27445 AN: 837656

Other (OTH) AF: 0.0364 AC: 1762 AN: 48468

GnomAD4 genome AF: 0.0575 AC: 8754 AN: 152252 Hom.: 397 Cov.: 32 AF XY: 0.0554 AC XY: 4124 AN XY: 74456

African (AFR) AF: 0.127 AC: 5266 AN: 41530

American (AMR) AF: 0.0326 AC: 498 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5186

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4820

European-Finnish (FIN) AF: 0.0253 AC: 269 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0336 AC: 2284 AN: 68024

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0411 Hom.: 71

Bravo AF: 0.0603

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.77
PhyloP100		0.21
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2307479;

hg19: chr2-37362555;