2-88575373-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004836.7(EIF2AK3):c.2110G>T(p.Ala704Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,613,760 control chromosomes in the GnomAD database, including 421,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45971 hom., cov: 32)

Exomes 𝑓: 0.71 ( 375836 hom. )

Consequence

EIF2AK3
NM_004836.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.73

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 links:

ENSG00000225420 (HGNC:58177):

ENSG00000225420 links:

LOC101928371 (HGNC:):

LOC101928371 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.5892735E-7).

BP6

Variant 2-88575373-C-A is Benign according to our data. Variant chr2-88575373-C-A is described in ClinVar as [Benign]. Clinvar id is 128986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-88575373-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7 link	c.2110G>T	p.Ala704Ser	missense_variant	Exon 13 of 17	ENST00000303236.9	NP_004827.4	Q9NZJ5B3KY45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9 link	c.2110G>T	p.Ala704Ser	missense_variant	Exon 13 of 17	1	NM_004836.7	ENSP00000307235.3		Q9NZJ5

Frequencies

GnomAD3 genomes

AF:

0.768

AC:

116690

AN:

151990

Hom.:

45919

Cov.:

show subpopulations

Gnomad AFR

AF:

0.944

Gnomad AMI

AF:

0.674

Gnomad AMR

AF:

0.682

Gnomad ASJ

AF:

0.784

Gnomad EAS

AF:

0.525

Gnomad SAS

AF:

0.618

Gnomad FIN

AF:

0.653

Gnomad MID

AF:

0.752

Gnomad NFE

AF:

0.728

Gnomad OTH

AF:

0.724

GnomAD3 exomes

AF:

0.698

AC:

175097

AN:

251010

Hom.:

62288

AF XY:

0.692

AC XY:

93914

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.951

Gnomad AMR exome

AF:

0.679

Gnomad ASJ exome

AF:

0.777

Gnomad EAS exome

AF:

0.504

Gnomad SAS exome

AF:

0.619

Gnomad FIN exome

AF:

0.653

Gnomad NFE exome

AF:

0.721

Gnomad OTH exome

AF:

0.694

GnomAD4 exome

AF:

0.714

AC:

1044020

AN:

1461652

Hom.:

375836

Cov.:

AF XY:

0.712

AC XY:

517684

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.953

Gnomad4 AMR exome

AF:

0.678

Gnomad4 ASJ exome

AF:

0.770

Gnomad4 EAS exome

AF:

0.548

Gnomad4 SAS exome

AF:

0.620

Gnomad4 FIN exome

AF:

0.657

Gnomad4 NFE exome

AF:

0.723

Gnomad4 OTH exome

AF:

0.723

GnomAD4 genome

AF:

0.768

AC:

116797

AN:

152108

Hom.:

45971

Cov.:

AF XY:

0.759

AC XY:

56399

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.945

Gnomad4 AMR

AF:

0.682

Gnomad4 ASJ

AF:

0.784

Gnomad4 EAS

AF:

0.526

Gnomad4 SAS

AF:

0.616

Gnomad4 FIN

AF:

0.653

Gnomad4 NFE

AF:

0.728

Gnomad4 OTH

AF:

0.722

Alfa

AF:

0.730

Hom.:

77476

Bravo

AF:

0.780

TwinsUK

AF:

0.716

AC:

2654

ALSPAC

AF:

0.719

AC:

2771

ESP6500AA

AF:

0.942

AC:

4150

ESP6500EA

AF:

0.730

AC:

6277

ExAC

AF:

0.702

AC:

85213

Asia WGS

AF:

0.630

AC:

2194

AN:

3478

EpiCase

AF:

0.736

EpiControl

AF:

0.731

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

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. -

not provided

Benign:3

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wolcott-Rallison dysplasia

Benign:3

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.080

.;T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.067

.;T;.

MetaRNN

Benign

5.6e-7

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.090

.;N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.099

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0030

.;B;.

Vest4

0.034

MPC

0.31

ClinPred

0.0043

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over