chr2-37107286-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001135651.3(EIF2AK2):c.1643G>A(p.Arg548Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

EIF2AK2
NM_001135651.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.18

Publications

5 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, Labcorp Genetics (formerly Invitae), G2P, Illumina
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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14152834).

BS2

High AC in GnomAd4 at 8 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.1643G>A	p.Arg548Gln	missense	Exon 17 of 17	NP_001129123.1	P19525-1
EIF2AK2	NM_002759.4		c.1643G>A	p.Arg548Gln	missense	Exon 17 of 17	NP_002750.1	P19525-1
EIF2AK2	NM_001135652.2		c.1520G>A	p.Arg507Gln	missense	Exon 14 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.1643G>A	p.Arg548Gln	missense	Exon 17 of 17	ENSP00000233057.4	P19525-1
EIF2AK2	ENST00000405334.5	TSL:1	c.1520G>A	p.Arg507Gln	missense	Exon 14 of 14	ENSP00000385014.1	P19525-2
EIF2AK2	ENST00000395127.6	TSL:5	c.1643G>A	p.Arg548Gln	missense	Exon 17 of 17	ENSP00000378559.2	P19525-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250250

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460766

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726520

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111748

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000525

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41556

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

PhyloP100

-1.2

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.2

REVEL

Benign

0.20

Sift

Uncertain

0.025

Sift4G

Uncertain

0.046

Polyphen

1.0

Vest4

0.095

MVP

0.89

MPC

0.86

ClinPred

0.50

GERP RS

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.44

Mutation Taster

=87/13

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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