Variant 2-88627121-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000303236.9(EIF2AK3):c.154G>T(p.Ala52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000592 in 1,350,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A52T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

EIF2AK3
ENST00000303236.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.21937218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EIF2AK3	NM_004836.7 linkuse as main transcript	c.154G>T	p.Ala52Ser	missense_variant	1/17	ENST00000303236.9	NP_004827.4
EIF2AK3	XM_047446430.1 linkuse as main transcript	c.154G>T	p.Ala52Ser	missense_variant	1/12		XP_047302386.1
EIF2AK3	XM_047446428.1 linkuse as main transcript	c.17+568G>T		intron_variant			XP_047302384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EIF2AK3	ENST00000303236.9 linkuse as main transcript	c.154G>T	p.Ala52Ser	missense_variant	1/17	1	NM_004836.7	ENSP00000307235	P1
EIF2AK3	ENST00000682892.1 linkuse as main transcript	c.-145-13268G>T		intron_variant				ENSP00000507214
EIF2AK3	ENST00000652099.1 linkuse as main transcript	c.154G>T	p.Ala52Ser	missense_variant, NMD_transcript_variant	1/18			ENSP00000498211
EIF2AK3	ENST00000652423.1 linkuse as main transcript	c.126+28G>T		intron_variant, NMD_transcript_variant				ENSP00000498948

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000592

AC:

AN:

1350788

Hom.:

Cov.:

AF XY:

0.00000600

AC XY:

AN XY:

666296

show subpopulations

Gnomad4 AFR exome

AF:

0.0000362

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000657

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000395

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.11

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.050

REVEL

Benign

0.083

Sift

Benign

0.34

Sift4G

Benign

0.51

Polyphen

0.011

Vest4

0.20

MutPred

0.16

Gain of glycosylation at A52 (P = 0.0015);

MVP

0.85

MPC

1.4

ClinPred

0.32

GERP RS

3.6

Varity_R

0.084

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over