2-88576576-C-G

Variant names:

• chr2-88576576-C-G
• rs35226268
• NM_004836.7:c.2014G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004836.7(EIF2AK3):​c.2014G>C​(p.Glu672Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E672K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19842613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7	c.2014G>C	p.Glu672Gln	missense_variant	Exon 12 of 17	ENST00000303236.9	NP_004827.4
EIF2AK3	NM_001313915.2	c.1561G>C	p.Glu521Gln	missense_variant	Exon 12 of 17		NP_001300844.1
EIF2AK3	XM_047446428.1	c.1723G>C	p.Glu575Gln	missense_variant	Exon 12 of 17		XP_047302384.1
EIF2AK3	XM_047446429.1	c.1330G>C	p.Glu444Gln	missense_variant	Exon 10 of 15		XP_047302385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.2014G>C	p.Glu672Gln	missense_variant	Exon 12 of 17	1	NM_004836.7	ENSP00000307235.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	.;T;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.34	.;N;.
PhyloP100		2.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.19	N;N;N
REVEL	Benign	0.079
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.42	T;T;.
Polyphen		0.14	.;B;.
Vest4		0.085
MutPred		0.37		.;Loss of catalytic residue at W674 (P = 0.0557);.;
MVP		0.71
MPC		0.36
ClinPred		0.47	T
GERP RS		5.4
Varity_R		0.089
gMVP		0.32
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs35226268; hg19: chr2-88876094;