chr2-88557424-C-CTA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_004836.7(EIF2AK3):​c.*311_*312insTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 356,034 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0061 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0078 ( 5 hom. )

Consequence

EIF2AK3
NM_004836.7 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.564
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00611 (926/151544) while in subpopulation NFE AF= 0.00819 (555/67790). AF 95% confidence interval is 0.00762. There are 1 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EIF2AK3NM_004836.7 linkuse as main transcriptc.*311_*312insTA 3_prime_UTR_variant 17/17 ENST00000303236.9
LOC101928371NR_110236.1 linkuse as main transcriptn.651-17078_651-17077dup intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EIF2AK3ENST00000303236.9 linkuse as main transcriptc.*311_*312insTA 3_prime_UTR_variant 17/171 NM_004836.7 P1
ENST00000413234.1 linkuse as main transcriptn.651-17078_651-17077dup intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
AF:
0.00612
AC:
926
AN:
151426
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00160
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00678
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.000416
Gnomad FIN
AF:
0.0173
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00819
Gnomad OTH
AF:
0.00867
GnomAD4 exome
AF:
0.00776
AC:
1587
AN:
204490
Hom.:
5
Cov.:
0
AF XY:
0.00724
AC XY:
785
AN XY:
108466
show subpopulations
Gnomad4 AFR exome
AF:
0.00235
Gnomad4 AMR exome
AF:
0.00747
Gnomad4 ASJ exome
AF:
0.00214
Gnomad4 EAS exome
AF:
0.00188
Gnomad4 SAS exome
AF:
0.00208
Gnomad4 FIN exome
AF:
0.0151
Gnomad4 NFE exome
AF:
0.00967
Gnomad4 OTH exome
AF:
0.00708
GnomAD4 genome
AF:
0.00611
AC:
926
AN:
151544
Hom.:
1
Cov.:
32
AF XY:
0.00656
AC XY:
486
AN XY:
74048
show subpopulations
Gnomad4 AFR
AF:
0.00160
Gnomad4 AMR
AF:
0.00677
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.000417
Gnomad4 FIN
AF:
0.0173
Gnomad4 NFE
AF:
0.00819
Gnomad4 OTH
AF:
0.00858
Bravo
AF:
0.00532
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Wolcott-Rallison dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs767645334; hg19: chr2-88856942; API