chr2-88627211-CCAGCAGCAG-C
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3
The NM_004836.7(EIF2AK3):c.55_63delCTGCTGCTG(p.Leu19_Leu21del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,278,450 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 0)
Exomes 𝑓: 0.000025 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
EIF2AK3
NM_004836.7 conservative_inframe_deletion
NM_004836.7 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.66
Publications
1 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 syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp, G2P
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP3
Nonframeshift variant in repetitive region in NM_004836.7
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004836.7. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| EIF2AK3 | NM_004836.7 | MANE Select | c.55_63delCTGCTGCTG | p.Leu19_Leu21del | conservative_inframe_deletion | Exon 1 of 17 | NP_004827.4 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| EIF2AK3 | ENST00000303236.9 | TSL:1 MANE Select | c.55_63delCTGCTGCTG | p.Leu19_Leu21del | conservative_inframe_deletion | Exon 1 of 17 | ENSP00000307235.3 | ||
| EIF2AK3 | ENST00000682892.1 | c.-145-13367_-145-13359delCTGCTGCTG | intron | N/A | ENSP00000507214.1 | ||||
| EIF2AK3 | ENST00000652099.1 | n.52_60delCTGCTGCTG | non_coding_transcript_exon | Exon 1 of 18 | ENSP00000498211.1 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 151044Hom.: 0 Cov.: 0
GnomAD3 genomes
AF:
AC:
0
AN:
151044
Hom.:
Cov.:
0
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad EAS
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Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
AF:
GnomAD2 exomes AF: 0.0000460 AC: 3AN: 65220 AF XY: 0.0000804 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
65220
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000250 AC: 32AN: 1278450Hom.: 0 AF XY: 0.0000270 AC XY: 17AN XY: 629790 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
32
AN:
1278450
Hom.:
AF XY:
AC XY:
17
AN XY:
629790
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
25608
American (AMR)
AF:
AC:
4
AN:
25570
Ashkenazi Jewish (ASJ)
AF:
AC:
1
AN:
22632
East Asian (EAS)
AF:
AC:
1
AN:
27396
South Asian (SAS)
AF:
AC:
3
AN:
70428
European-Finnish (FIN)
AF:
AC:
2
AN:
30920
Middle Eastern (MID)
AF:
AC:
0
AN:
3816
European-Non Finnish (NFE)
AF:
AC:
20
AN:
1019104
Other (OTH)
AF:
AC:
1
AN:
52976
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.323
Heterozygous variant carriers
0
3
7
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14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
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Age
GnomAD4 genome 0.00 AC: 0AN: 151044Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 73738
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
151044
Hom.:
Cov.:
0
AF XY:
AC XY:
0
AN XY:
73738
African (AFR)
AF:
AC:
0
AN:
41216
American (AMR)
AF:
AC:
0
AN:
15196
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3456
East Asian (EAS)
AF:
AC:
0
AN:
5088
South Asian (SAS)
AF:
AC:
0
AN:
4808
European-Finnish (FIN)
AF:
AC:
0
AN:
10342
Middle Eastern (MID)
AF:
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67636
Other (OTH)
AF:
AC:
0
AN:
2080
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
1
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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