Genetic Variant NM_001135651.3:c.785+72A>C (chr2-37135412-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.214

Publications

3 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: 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)

EIF2AK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK2	NM_001135651.3 link	c.785+72A>C		intron_variant	Intron 10 of 16	ENST00000233057.9	NP_001129123.1	P19525-1Q8IW76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK2	ENST00000233057.9 link	c.785+72A>C		intron_variant	Intron 10 of 16	2	NM_001135651.3	ENSP00000233057.4		P19525-1

Frequencies

GnomAD3 genomes

AF:

0.0574

AC:

8729

AN:

152134

Hom.:

394

Cov.:

show subpopulations

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

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1775

3549

5324

7098

8873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

940

1880

2820

3760

4700

<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:

0.0575

AC:

8754

AN:

152252

Hom.:

397

Cov.:

AF XY:

0.0554

AC XY:

4124

AN XY:

74456

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0336

AC:

2284

AN:

68024

Other (OTH)

AF:

0.0445

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

398

796

1193

1591

1989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0411

Hom.:

Bravo

AF:

0.0603

Asia WGS

AF:

0.0230

AC:

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

6.0

(source)

DANN

Benign

0.77

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over