2-88585840-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004836.7(EIF2AK3):​c.1650+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

EIF2AK3
NM_004836.7 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 6.07
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-88585840-C-T is Pathogenic according to our data. Variant chr2-88585840-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 445635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EIF2AK3NM_004836.7 linkuse as main transcriptc.1650+1G>A splice_donor_variant, intron_variant ENST00000303236.9 NP_004827.4 Q9NZJ5B3KY45

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EIF2AK3ENST00000303236.9 linkuse as main transcriptc.1650+1G>A splice_donor_variant, intron_variant 1 NM_004836.7 ENSP00000307235.3 Q9NZJ5

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 31, 2023ClinVar contains an entry for this variant (Variation ID: 445635). This variant has not been reported in the literature in individuals affected with EIF2AK3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the EIF2AK3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EIF2AK3 are known to be pathogenic (PMID: 11997520). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -
Likely pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 19, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
33
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
MutationTaster
Benign
1.0
D;D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.86
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.86
Position offset: 1

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.

Other links and lift over

dbSNP: rs1205989324; hg19: chr2-88885358; COSMIC: COSV57546783; COSMIC: COSV57546783; API