2-88613755-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.89

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=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	UniProt
EIF2AK3	NM_004836.7	c.407C>G	p.Ser136Cys	missense_variant	2/17	ENST00000303236.9
EIF2AK3	XM_047446428.1	c.116C>G	p.Ser39Cys	missense_variant	2/17
EIF2AK3	XM_047446430.1	c.407C>G	p.Ser136Cys	missense_variant	2/12
EIF2AK3	NM_001313915.2	c.-47C>G		5_prime_UTR_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK3	ENST00000303236.9	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.: 32

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

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.: 35 AF XY: 0.288 AC XY: 209247 AN XY: 726798

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.: 32 AF XY: 0.242 AC XY: 18003 AN XY: 74284

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	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	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

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	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.0099
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.00056	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.13	P;P
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.061
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.0020	B
Vest4		0.079
MPC		0.34
ClinPred		0.015	T
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

Other links and lift over

dbSNP: rs867529; hg19: chr2-88913273; COSMIC: COSV57546254;