Genetic Variant EIF2AK2:c.-183-125C>T (chr2-37149148-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001135651.3(EIF2AK2):c.-183-125C>T variant causes a intron change. The variant allele was found at a frequency of 0.401 in 949,826 control chromosomes in the GnomAD database, including 83,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10875 hom., cov: 31)

Exomes 𝑓: 0.41 ( 72348 hom. )

Consequence

EIF2AK2
NM_001135651.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.69

Publications

30 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 links:

ARL14EPP1 (HGNC:54676): (ARL14EP pseudogene 1)

ARL14EPP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 2-37149148-G-A is Benign according to our data. Variant chr2-37149148-G-A is described in ClinVar as Benign. ClinVar VariationId is 1315570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK2	NM_001135651.3 link	c.-183-125C>T		intron_variant	Intron 1 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.-183-125C>T		intron_variant	Intron 1 of 16	2	NM_001135651.3	ENSP00000233057.4		P19525-1

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

53211

AN:

151888

Hom.:

10876

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.364

Gnomad ASJ

AF:

0.446

Gnomad EAS

AF:

0.763

Gnomad SAS

AF:

0.313

Gnomad FIN

AF:

0.514

Gnomad MID

AF:

0.343

Gnomad NFE

AF:

0.407

Gnomad OTH

AF:

0.384

GnomAD4 exome

AF:

0.411

AC:

328051

AN:

797820

Hom.:

72348

Cov.:

AF XY:

0.406

AC XY:

171765

AN XY:

422772

show subpopulations

African (AFR)

AF:

0.152

AC:

3155

AN:

20732

American (AMR)

AF:

0.356

AC:

15487

AN:

43460

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

9370

AN:

21766

East Asian (EAS)

AF:

0.801

AC:

29398

AN:

36714

South Asian (SAS)

AF:

0.290

AC:

21048

AN:

72632

European-Finnish (FIN)

AF:

0.493

AC:

25894

AN:

52518

Middle Eastern (MID)

AF:

0.376

AC:

1662

AN:

4420

European-Non Finnish (NFE)

AF:

0.407

AC:

206557

AN:

507476

Other (OTH)

AF:

0.406

AC:

15480

AN:

38102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

9679

19358

29038

38717

48396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3666

7332

10998

14664

18330

<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:

0.350

AC:

53215

AN:

152006

Hom.:

10875

Cov.:

AF XY:

0.359

AC XY:

26680

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.154

AC:

6376

AN:

41486

American (AMR)

AF:

0.364

AC:

5555

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.446

AC:

1545

AN:

3466

East Asian (EAS)

AF:

0.764

AC:

3945

AN:

5166

South Asian (SAS)

AF:

0.313

AC:

1507

AN:

4814

European-Finnish (FIN)

AF:

0.514

AC:

5425

AN:

10550

Middle Eastern (MID)

AF:

0.348

AC:

101

AN:

290

European-Non Finnish (NFE)

AF:

0.407

AC:

27676

AN:

67948

Other (OTH)

AF:

0.388

AC:

817

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1619

3239

4858

6478

8097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.351

Hom.:

5040

Bravo

AF:

0.338

Asia WGS

AF:

0.500

AC:

1739

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 02, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.1

(source)

DANN

Benign

0.67

PhyloP100

3.7

PromoterAI

-0.034

Neutral

(source)

Mutation Taster

=293/7

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over