chr2-88595662-A-C

Variant names:

• chr2-88595662-A-C
• rs1057524886
• NM_004836.7:c.440T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004836.7(EIF2AK3):​c.440T>G​(p.Val147Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V147V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK3 NM_004836.7 missense, splice_region
• Scores: Splicing: ADA: 0.04474
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.82
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Wolcott-Rallison syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7	c.440T>G	p.Val147Gly	missense_variant, splice_region_variant	Exon 3 of 17	ENST00000303236.9	NP_004827.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.440T>G	p.Val147Gly	missense_variant, splice_region_variant	Exon 3 of 17	1	NM_004836.7	ENSP00000307235.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Monogenic diabetes Uncertain:1

Apr 07, 2015

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T;.
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		6.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;.
Polyphen		1.0	D;.
Vest4		0.63
MutPred		0.55		Loss of stability (P = 0.01);.;
MVP		0.88
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
PromoterAI		-0.011	Neutral
Varity_R		0.78
gMVP		0.91
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.045
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057524886; hg19: chr2-88895180;