Genetic Variant NM_001135651.3:c.1413C>G (chr2-37109260-G-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001135651.3(EIF2AK2):c.1413C>G(p.Leu471Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,613,908 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 78 hom., cov: 32)

Exomes 𝑓: 0.031 ( 766 hom. )

Consequence

EIF2AK2
NM_001135651.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0120

Publications

6 publications found

Variant links:

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)

EIF2AK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 2-37109260-G-C is Benign according to our data. Variant chr2-37109260-G-C is described in ClinVar as Benign. ClinVar VariationId is 1571185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.012 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0292 (4447/152306) while in subpopulation NFE AF = 0.0323 (2196/68030). AF 95% confidence interval is 0.0312. There are 78 homozygotes in GnomAd4. There are 2103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4447 AD,Unknown gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2AK2	NM_001135651.3	MANE Select	c.1413C>G	p.Leu471Leu	synonymous	Exon 15 of 17	NP_001129123.1	P19525-1
EIF2AK2	NM_002759.4		c.1413C>G	p.Leu471Leu	synonymous	Exon 15 of 17	NP_002750.1	P19525-1
EIF2AK2	NM_001135652.2		c.1290C>G	p.Leu430Leu	synonymous	Exon 12 of 14	NP_001129124.1	P19525-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2AK2	ENST00000233057.9	TSL:2 MANE Select	c.1413C>G	p.Leu471Leu	synonymous	Exon 15 of 17	ENSP00000233057.4	P19525-1
EIF2AK2	ENST00000405334.5	TSL:1	c.1290C>G	p.Leu430Leu	synonymous	Exon 12 of 14	ENSP00000385014.1	P19525-2
EIF2AK2	ENST00000395127.6	TSL:5	c.1413C>G	p.Leu471Leu	synonymous	Exon 15 of 17	ENSP00000378559.2	P19525-1

Frequencies

GnomAD3 genomes

AF:

0.0291

AC:

4436

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.0352

Gnomad EAS

AF:

0.000960

Gnomad SAS

AF:

0.0319

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0323

Gnomad OTH

AF:

0.0320

GnomAD2 exomes

AF:

0.0287

AC:

7204

AN:

251330

AF XY:

0.0301

show subpopulations

Gnomad AFR exome

AF:

0.0273

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0387

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0327

Gnomad OTH exome

AF:

0.0368

GnomAD4 exome

AF:

0.0308

AC:

45044

AN:

1461602

Hom.:

766

Cov.:

AF XY:

0.0315

AC XY:

22904

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0303

AC:

1015

AN:

33478

American (AMR)

AF:

0.0198

AC:

887

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

1016

AN:

26128

East Asian (EAS)

AF:

0.000580

AC:

AN:

39684

South Asian (SAS)

AF:

0.0404

AC:

3481

AN:

86230

European-Finnish (FIN)

AF:

0.0241

AC:

1286

AN:

53416

Middle Eastern (MID)

AF:

0.0404

AC:

233

AN:

5768

European-Non Finnish (NFE)

AF:

0.0317

AC:

35254

AN:

1111798

Other (OTH)

AF:

0.0306

AC:

1849

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

2158

4316

6473

8631

10789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1286

2572

3858

5144

6430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0292

AC:

4447

AN:

152306

Hom.:

Cov.:

AF XY:

0.0282

AC XY:

2103

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0291

AC:

1208

AN:

41566

American (AMR)

AF:

0.0226

AC:

345

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

122

AN:

3470

East Asian (EAS)

AF:

0.000963

AC:

AN:

5194

South Asian (SAS)

AF:

0.0317

AC:

153

AN:

4826

European-Finnish (FIN)

AF:

0.0253

AC:

268

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0323

AC:

2196

AN:

68030

Other (OTH)

AF:

0.0312

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

218

437

655

874

1092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0325

Hom.:

Bravo

AF:

0.0287

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0342

EpiControl

AF:

0.0316

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

5.2

(source)

DANN

Benign

0.72

PhyloP100

-0.012

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over