rs35226268

chr2-88576576-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004836.7(EIF2AK3):c.2014G>A(p.Glu672Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,120 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (23 hom.)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.37

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054520965).
• BP6: Variant 2-88576576-C-T is Benign according to our data. Variant chr2-88576576-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 337410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000978 (149/152282) while in subpopulation EAS AF= 0.0219 (113/5170). AF 95% confidence interval is 0.0186. There are 2 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK3	NM_004836.7	c.2014G>A	p.Glu672Lys	missense_variant	12/17	ENST00000303236.9
EIF2AK3	NM_001313915.2	c.1561G>A	p.Glu521Lys	missense_variant	12/17
EIF2AK3	XM_047446428.1	c.1723G>A	p.Glu575Lys	missense_variant	12/17
EIF2AK3	XM_047446429.1	c.1330G>A	p.Glu444Lys	missense_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.2014G>A	p.Glu672Lys	missense_variant	12/17	1	NM_004836.7	P1

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00203 AC: 509 AN: 251252 Hom.: 4 AF XY: 0.00194 AC XY: 263 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0234

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00104 AC: 1522 AN: 1461838 Hom.: 23 Cov.: 31 AF XY: 0.00102 AC XY: 741 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0313

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00221

Gnomad4 NFE exome AF: 0.0000827

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0219

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000632 Hom.: 1

Bravo AF: 0.000986

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00215 AC: 261

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Wolcott-Rallison dysplasia Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 31, 2023	- -

EIF2AK3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.12	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.59	T;T;T
Sift4G	Benign	0.96	T;T;.
Polyphen		0.022	.;B;.
Vest4		0.30
MVP		0.69
MPC		0.39
ClinPred		0.032	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.35

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

Other links and lift over

dbSNP: rs35226268; hg19: chr2-88876094; COSMIC: COSV57548977; COSMIC: COSV57548977;