2-88627121-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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. A52A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (20 hom.)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.56

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=0.0064079165).
• 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 GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK3	NM_004836.7	c.154G>A	p.Ala52Thr	missense_variant	1/17	ENST00000303236.9
EIF2AK3	XM_047446430.1	c.154G>A	p.Ala52Thr	missense_variant	1/12
EIF2AK3	XM_047446428.1	c.17+568G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.154G>A	p.Ala52Thr	missense_variant	1/17	1	NM_004836.7	P1
EIF2AK3	ENST00000682892.1	c.-145-13268G>A		intron_variant
EIF2AK3	ENST00000652099.1	c.154G>A	p.Ala52Thr	missense_variant, NMD_transcript_variant	1/18
EIF2AK3	ENST00000652423.1	c.126+28G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 544 AN: 151980 Hom.: 1 Cov.: 33

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.: 5 AF XY: 0.00483 AC XY: 262 AN XY: 54288

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.: 20 Cov.: 30 AF XY: 0.00472 AC XY: 3147 AN XY: 666292

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.: 1 Cov.: 33 AF XY: 0.00359 AC XY: 267 AN XY: 74374

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.: 0

Bravo AF: 0.00287

ExAC AF: 0.00377 AC: 286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 08, 2021	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	EIF2AK3: PP2, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Wolcott-Rallison dysplasia Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 17, 2022	- -

EIF2AK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

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

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 20, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.069
Sift	Benign	0.19	T
Sift4G	Benign	0.31	T
Polyphen		0.29	B
Vest4		0.20
MVP		0.88
MPC		1.5
ClinPred		0.021	T
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

Other links and lift over

dbSNP: rs201593811; hg19: chr2-88926639;