2-88595605-T-A

Position:

• chr2-88595605-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004836.7(EIF2AK3):​c.497A>T​(p.Gln166Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. Q166R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21324241).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK3	NM_004836.7	c.497A>T	p.Gln166Leu	missense_variant	3/17	ENST00000303236.9
EIF2AK3	NM_001313915.2	c.44A>T	p.Gln15Leu	missense_variant	3/17
EIF2AK3	XM_047446428.1	c.206A>T	p.Gln69Leu	missense_variant	3/17
EIF2AK3	XM_047446430.1	c.497A>T	p.Gln166Leu	missense_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.497A>T	p.Gln166Leu	missense_variant	3/17	1	NM_004836.7	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	.;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	0.0091
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	.;T;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.15	T;T;.
Polyphen		0.0010	.;B;.
Vest4		0.32
MutPred		0.49		.;Gain of sheet (P = 0.0101);.;
MVP		0.82
MPC		0.33
ClinPred		0.58	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.75

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: rs13045; hg19: chr2-88895123;