2-88583496-T-A

Position:

chr2-88583496-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000303236.9(EIF2AK3):c.1697A>T(p.Asp566Val) variant causes a missense change. The variant allele was found at a frequency of 0.00415 in 1,613,262 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D566G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 20 hom. )

Consequence

EIF2AK3
ENST00000303236.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 7.12

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009609789).

BP6

Variant 2-88583496-T-A is Benign according to our data. Variant chr2-88583496-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 337412.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=6, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00258 (393/152294) while in subpopulation NFE AF= 0.00453 (308/68016). AF 95% confidence interval is 0.00411. There are 0 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK3	NM_004836.7 linkuse as main transcript	c.1697A>T	p.Asp566Val	missense_variant	10/17	ENST00000303236.9	NP_004827.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9 linkuse as main transcript	c.1697A>T	p.Asp566Val	missense_variant	10/17	1	NM_004836.7	ENSP00000307235	P1

Frequencies

GnomAD3 genomes

AF:

0.00258

AC:

393

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00260

AC:

653

AN:

250846

Hom.:

AF XY:

0.00249

AC XY:

337

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00256

Gnomad NFE exome

AF:

0.00490

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00432

AC:

6307

AN:

1460968

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

3015

AN XY:

726836

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00331

Gnomad4 NFE exome

AF:

0.00533

Gnomad4 OTH exome

AF:

0.00229

GnomAD4 genome

AF:

0.00258

AC:

393

AN:

152294

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00453

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00348

Hom.:

Bravo

AF:

0.00246

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00264

AC:

321

EpiCase

AF:

0.00376

EpiControl

AF:

0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	EIF2AK3: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2016	- -

Wolcott-Rallison dysplasia

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	The EIF2AK3 c.1697A>T; p.Asp566Val variant (rs55791823), to our knowledge, is not reported in the medical literature in individuals with Wolcott-Rallison syndrome. This variant is reported in ClinVar (Variation ID: 337412) and is found in the general population with an overall allele frequency of 0.26% (730/282,242 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.384). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 21, 2019

- -

Connective tissue disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

EIF2AK3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2023

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

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 18, 2019

ACMG criteria: BA1 (0.5% in EurNF in gnomAD), BS2 (1 homozygotes in gnomAD)= benign (REVEL 0.384 + PP3/4 predictors) + BP4/5 predictors= conflicting evidence, not using) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

.;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

.;D;.

M_CAP

Benign

0.076

MetaRNN

Benign

0.0096

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.8

.;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.8

N;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.015

D;D;D

Sift4G

Benign

0.29

T;T;.

Polyphen

0.99

.;D;.

Vest4

0.52

MVP

0.91

MPC

0.52

ClinPred

0.017

GERP RS

5.7

Varity_R

0.22

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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