2-88613755-G-C

Position:

chr2-88613755-G-C

Variant summary

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

The NM_004836.7(EIF2AK3):c.407C>G(p.Ser136Cys) variant causes a missense change. The variant allele was found at a frequency of 0.281 in 1,612,796 control chromosomes in the GnomAD database, including 67,908 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 Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5255 hom., cov: 32)

Exomes 𝑓: 0.29 ( 62653 hom. )

Consequence

EIF2AK3
NM_004836.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.89

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=5.620122E-4).

BP6

Variant 2-88613755-G-C is Benign according to our data. Variant chr2-88613755-G-C is described in ClinVar as [Benign]. Clinvar id is 128987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EIF2AK3	NM_004836.7 linkuse as main transcript	c.407C>G	p.Ser136Cys	missense_variant	2/17	ENST00000303236.9
EIF2AK3	XM_047446428.1 linkuse as main transcript	c.116C>G	p.Ser39Cys	missense_variant	2/17
EIF2AK3	XM_047446430.1 linkuse as main transcript	c.407C>G	p.Ser136Cys	missense_variant	2/12
EIF2AK3	NM_001313915.2 linkuse as main transcript	c.-47C>G		5_prime_UTR_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK3	ENST00000303236.9 linkuse as main transcript	c.407C>G	p.Ser136Cys	missense_variant	2/17	1	NM_004836.7	P1

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35361

AN:

151874

Hom.:

5251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0557

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.320

Gnomad ASJ

AF:

0.219

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.385

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.272

Gnomad OTH

AF:

0.278

GnomAD3 exomes

AF:

0.303

AC:

76063

AN:

251374

Hom.:

12733

AF XY:

0.308

AC XY:

41840

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0487

Gnomad AMR exome

AF:

0.322

Gnomad ASJ exome

AF:

0.225

Gnomad EAS exome

AF:

0.496

Gnomad SAS exome

AF:

0.381

Gnomad FIN exome

AF:

0.348

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.306

GnomAD4 exome

AF:

0.286

AC:

417171

AN:

1460804

Hom.:

62653

Cov.:

AF XY:

0.288

AC XY:

209247

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.0468

Gnomad4 AMR exome

AF:

0.323

Gnomad4 ASJ exome

AF:

0.232

Gnomad4 EAS exome

AF:

0.453

Gnomad4 SAS exome

AF:

0.380

Gnomad4 FIN exome

AF:

0.343

Gnomad4 NFE exome

AF:

0.277

Gnomad4 OTH exome

AF:

0.278

GnomAD4 genome

AF:

0.233

AC:

35372

AN:

151992

Hom.:

5255

Cov.:

AF XY:

0.242

AC XY:

18003

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0555

Gnomad4 AMR

AF:

0.320

Gnomad4 ASJ

AF:

0.219

Gnomad4 EAS

AF:

0.474

Gnomad4 SAS

AF:

0.387

Gnomad4 FIN

AF:

0.349

Gnomad4 NFE

AF:

0.272

Gnomad4 OTH

AF:

0.280

Alfa

AF:

0.265

Hom.:

4347

Bravo

AF:

0.220

TwinsUK

AF:

0.284

AC:

1053

ALSPAC

AF:

0.281

AC:

1083

ESP6500AA

AF:

0.0581

AC:

256

ESP6500EA

AF:

0.270

AC:

2324

ExAC

AF:

0.298

AC:

36209

Asia WGS

AF:

0.370

AC:

1284

AN:

3478

EpiCase

AF:

0.263

EpiControl

AF:

0.269

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Wolcott-Rallison dysplasia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.23

Eigen

Benign

0.0099

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

MetaRNN

Benign

0.00056

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.13

P;P

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

REVEL

Benign

0.061

Sift

Benign

0.13

Sift4G

Benign

0.22

Polyphen

0.0020

Vest4

0.079

MPC

0.34

ClinPred

0.015

GERP RS

5.4

Varity_R

0.24

gMVP

0.56

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