chr2-88595605-T-C

Variant names:

Variant summary

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

The NM_004836.7(EIF2AK3):c.497A>G(p.Gln166Arg) variant causes a missense change. The variant allele was found at a frequency of 0.658 in 1,613,308 control chromosomes in the GnomAD database, including 353,757 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 38451 hom., cov: 31)

Exomes 𝑓: 0.65 ( 315306 hom. )

Consequence

EIF2AK3
NM_004836.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.57

Publications

54 publications found

Variant links:

Genes affected

EIF2AK3 (HGNC:3255): (eukaryotic translation initiation factor 2 alpha kinase 3) The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2, leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins. Mutations in this gene are associated with Wolcott-Rallison syndrome. [provided by RefSeq, Sep 2015]

EIF2AK3 Gene-Disease associations (from GenCC):

Wolcott-Rallison syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp, G2P

EIF2AK3 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 (MetaRNN=6.14049E-7).

BP6

Variant 2-88595605-T-C is Benign according to our data. Variant chr2-88595605-T-C is described in ClinVar as Benign. ClinVar VariationId is 128988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7 link	c.497A>G	p.Gln166Arg	missense_variant	Exon 3 of 17	ENST00000303236.9	NP_004827.4	Q9NZJ5B3KY45
EIF2AK3	NM_001313915.2 link	c.44A>G	p.Gln15Arg	missense_variant	Exon 3 of 17		NP_001300844.1	A0A804HIT4Q68DI6
EIF2AK3	XM_047446428.1 link	c.206A>G	p.Gln69Arg	missense_variant	Exon 3 of 17		XP_047302384.1
EIF2AK3	XM_047446430.1 link	c.497A>G	p.Gln166Arg	missense_variant	Exon 3 of 12		XP_047302386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9 link	c.497A>G	p.Gln166Arg	missense_variant	Exon 3 of 17	1	NM_004836.7	ENSP00000307235.3		Q9NZJ5

Frequencies

GnomAD3 genomes

AF:

0.703

AC:

106666

AN:

151836

Hom.:

38408

Cov.:

show subpopulations

Gnomad AFR

AF:

0.862

Gnomad AMI

AF:

0.656

Gnomad AMR

AF:

0.623

Gnomad ASJ

AF:

0.731

Gnomad EAS

AF:

0.490

Gnomad SAS

AF:

0.528

Gnomad FIN

AF:

0.592

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.669

Gnomad OTH

AF:

0.672

GnomAD2 exomes

AF:

0.632

AC:

158568

AN:

250952

AF XY:

0.628

show subpopulations

Gnomad AFR exome

AF:

0.870

Gnomad AMR exome

AF:

0.576

Gnomad ASJ exome

AF:

0.727

Gnomad EAS exome

AF:

0.468

Gnomad FIN exome

AF:

0.592

Gnomad NFE exome

AF:

0.667

Gnomad OTH exome

AF:

0.641

GnomAD4 exome

AF:

0.654

AC:

955218

AN:

1461354

Hom.:

315306

Cov.:

AF XY:

0.651

AC XY:

473352

AN XY:

726994

show subpopulations

African (AFR)

AF:

0.873

AC:

29242

AN:

33478

American (AMR)

AF:

0.581

AC:

25996

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.721

AC:

18839

AN:

26128

East Asian (EAS)

AF:

0.522

AC:

20700

AN:

39656

South Asian (SAS)

AF:

0.535

AC:

46133

AN:

86240

European-Finnish (FIN)

AF:

0.597

AC:

31884

AN:

53394

Middle Eastern (MID)

AF:

0.693

AC:

3998

AN:

5768

European-Non Finnish (NFE)

AF:

0.664

AC:

738413

AN:

1111608

Other (OTH)

AF:

0.663

AC:

40013

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

18131

36263

54394

72526

90657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19056

38112

57168

76224

95280

<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:

0.703

AC:

106758

AN:

151954

Hom.:

38451

Cov.:

AF XY:

0.694

AC XY:

51544

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.862

AC:

35743

AN:

41468

American (AMR)

AF:

0.622

AC:

9494

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.731

AC:

2533

AN:

3466

East Asian (EAS)

AF:

0.490

AC:

2529

AN:

5160

South Asian (SAS)

AF:

0.526

AC:

2529

AN:

4804

European-Finnish (FIN)

AF:

0.592

AC:

6233

AN:

10532

Middle Eastern (MID)

AF:

0.687

AC:

202

AN:

294

European-Non Finnish (NFE)

AF:

0.669

AC:

45485

AN:

67958

Other (OTH)

AF:

0.670

AC:

1413

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1500

3000

4500

6000

7500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.680

Hom.:

139115

Bravo

AF:

0.715

TwinsUK

AF:

0.656

AC:

2434

ALSPAC

AF:

0.663

AC:

2555

ESP6500AA

AF:

0.865

AC:

3811

ESP6500EA

AF:

0.668

AC:

5745

ExAC

AF:

0.637

AC:

77366

Asia WGS

AF:

0.564

AC:

1963

AN:

3478

EpiCase

AF:

0.684

EpiControl

AF:

0.681

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 21, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Wolcott-Rallison dysplasia

Benign:4

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24032041) -

Connective tissue disorder

Benign:1

Jul 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.080

.;T;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.20

.;T;.

MetaRNN

Benign

6.1e-7

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.0

.;N;.

PhyloP100

5.6

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.81

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.92

T;T;T

Sift4G

Benign

0.98

T;T;.

Polyphen

0.0

.;B;.

Vest4

0.057

MPC

0.36

ClinPred

0.013

GERP RS

6.2

PromoterAI

0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.67

Mutation Taster

=90/10

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