2-88627121-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004836.7(EIF2AK3):c.154G>A(p.Ala52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00468 in 1,502,868 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0048 ( 20 hom. )

Consequence

EIF2AK3
NM_004836.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.56

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:

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=0.0064079165).

BP6

Variant 2-88627121-C-T is Benign according to our data. Variant chr2-88627121-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 193296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-88627121-C-T is described in Lovd as [Likely_benign]. Variant chr2-88627121-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00359 (546/152088) while in subpopulation NFE AF= 0.00577 (392/67958). AF 95% confidence interval is 0.0053. There are 1 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7 link	c.154G>A	p.Ala52Thr	missense_variant	Exon 1 of 17	ENST00000303236.9	NP_004827.4	Q9NZJ5B3KY45
EIF2AK3	XM_047446430.1 link	c.154G>A	p.Ala52Thr	missense_variant	Exon 1 of 12		XP_047302386.1
EIF2AK3	XM_047446428.1 link	c.17+568G>A		intron_variant	Intron 1 of 16		XP_047302384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF2AK3	ENST00000303236.9 link	c.154G>A	p.Ala52Thr	missense_variant	Exon 1 of 17	1	NM_004836.7	ENSP00000307235.3	Q9NZJ5
EIF2AK3	ENST00000682892.1 link	c.-145-13268G>A		intron_variant	Intron 2 of 17			ENSP00000507214.1	A0A804HIT4
EIF2AK3	ENST00000652099.1 link	n.151G>A		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000498211.1	A0A494BZR8
EIF2AK3	ENST00000652423.1 link	n.126+28G>A		intron_variant	Intron 1 of 3			ENSP00000498948.1	A0A494C186

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

544

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00599

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00577

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00460

AC:

443

AN:

96344

Hom.:

AF XY:

0.00483

AC XY:

262

AN XY:

54288

show subpopulations

Gnomad AFR exome

AF:

0.00133

Gnomad AMR exome

AF:

0.00290

Gnomad ASJ exome

AF:

0.000147

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00317

Gnomad FIN exome

AF:

0.00863

Gnomad NFE exome

AF:

0.00703

Gnomad OTH exome

AF:

0.00830

GnomAD4 exome

AF:

0.00480

AC:

6483

AN:

1350780

Hom.:

Cov.:

AF XY:

0.00472

AC XY:

3147

AN XY:

666292

show subpopulations

Gnomad4 AFR exome

AF:

0.000868

Gnomad4 AMR exome

AF:

0.00277

Gnomad4 ASJ exome

AF:

0.000168

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00312

Gnomad4 FIN exome

AF:

0.00984

Gnomad4 NFE exome

AF:

0.00521

Gnomad4 OTH exome

AF:

0.00411

GnomAD4 genome

AF:

0.00359

AC:

546

AN:

152088

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

267

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00599

Gnomad4 NFE

AF:

0.00577

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00511

Hom.:

Bravo

AF:

0.00287

ExAC

AF:

0.00377

AC:

286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EIF2AK3: BS2 -

not specified

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wolcott-Rallison dysplasia

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Mar 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EIF2AK3-related disorder

Benign:1

Sep 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Monogenic diabetes

Benign:1

Jul 20, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BP4 (8 predictors + REVEL score 0.069; not using PP3 (2 predictors)),BS2 (5 homozygotes in gnomAD), BS1 (0.7% MAF in ENF, which is greater than 0.001 (estimated prevalence 1:1million)= benign -

Connective tissue disorder

Benign:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.25

REVEL

Benign

0.069

Sift

Benign

0.19

Sift4G

Benign

0.31

Polyphen

0.29

Vest4

0.20

MVP

0.88

MPC

1.5

ClinPred

0.021

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.078

gMVP

0.40

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