chr2-88627211-CCAGCAGCAG-C

Position:

chr2-88627211-CCAGCAGCAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_004836.7(EIF2AK3):c.55_63del(p.Leu19_Leu21del) variant causes a 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 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.66

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000025 (32/1278450) while in subpopulation AMR AF= 0.000156 (4/25570). AF 95% confidence interval is 0.0000534. There are 0 homozygotes in gnomad4_exome. There are 17 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EIF2AK3	NM_004836.7 linkuse as main transcript	c.55_63del	p.Leu19_Leu21del	inframe_deletion	1/17	ENST00000303236.9	NP_004827.4
EIF2AK3	XM_047446430.1 linkuse as main transcript	c.55_63del	p.Leu19_Leu21del	inframe_deletion	1/12		XP_047302386.1
EIF2AK3	XM_047446428.1 linkuse as main transcript	c.17+469_17+477del		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.55_63del	p.Leu19_Leu21del	inframe_deletion	1/17	1	NM_004836.7	ENSP00000307235	P1
EIF2AK3	ENST00000682892.1 linkuse as main transcript	c.-145-13367_-145-13359del		intron_variant				ENSP00000507214
EIF2AK3	ENST00000652099.1 linkuse as main transcript	c.53_61del	p.Leu19_Leu21del	inframe_deletion, NMD_transcript_variant	1/18			ENSP00000498211
EIF2AK3	ENST00000652423.1 linkuse as main transcript	c.55_63del	p.Leu19_Leu21del	inframe_deletion, NMD_transcript_variant	1/4			ENSP00000498948

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151044

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000460

AC:

AN:

65220

Hom.:

AF XY:

0.0000804

AC XY:

AN XY:

37308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000710

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000250

AC:

AN:

1278450

Hom.:

AF XY:

0.0000270

AC XY:

AN XY:

629790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000156

Gnomad4 ASJ exome

AF:

0.0000442

Gnomad4 EAS exome

AF:

0.0000365

Gnomad4 SAS exome

AF:

0.0000426

Gnomad4 FIN exome

AF:

0.0000647

Gnomad4 NFE exome

AF:

0.0000196

Gnomad4 OTH exome

AF:

0.0000189

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73738

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2023

This variant, c.55_63del, results in the deletion of 3 amino acid(s) of the EIF2AK3 protein (p.Leu19_Leu21del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with EIF2AK3-related conditions. -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over