Variant 2-88627211-CCAGCAGCAGCAG-CCAGCAGCAGCAGCAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_004836.7(EIF2AK3):c.63_64insCTG(p.Leu21dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

EIF2AK3
NM_004836.7 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.853

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 Likely_benign. Variant got -1 ACMG points.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000258 (39/151156) while in subpopulation SAS AF= 0.00167 (8/4804). AF 95% confidence interval is 0.000828. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 0. 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.63_64insCTG	p.Leu21dup	inframe_insertion	1/17	ENST00000303236.9	NP_004827.4
EIF2AK3	XM_047446430.1 linkuse as main transcript	c.63_64insCTG	p.Leu21dup	inframe_insertion	1/12		XP_047302386.1
EIF2AK3	XM_047446428.1 linkuse as main transcript	c.17+477_17+478insCTG		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.63_64insCTG	p.Leu21dup	inframe_insertion	1/17	1	NM_004836.7	ENSP00000307235	P1
EIF2AK3	ENST00000682892.1 linkuse as main transcript	c.-145-13359_-145-13358insCTG		intron_variant				ENSP00000507214
EIF2AK3	ENST00000652099.1 linkuse as main transcript	c.61_62insCTG	p.Leu21dup	inframe_insertion, NMD_transcript_variant	1/18			ENSP00000498211
EIF2AK3	ENST00000652423.1 linkuse as main transcript	c.63_64insCTG	p.Leu21dup	inframe_insertion, NMD_transcript_variant	1/4			ENSP00000498948

Frequencies

GnomAD3 genomes

AF:

0.000258

AC:

AN:

151044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000290

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000613

AC:

AN:

65220

Hom.:

AF XY:

0.000777

AC XY:

AN XY:

37308

show subpopulations

Gnomad AFR exome

AF:

0.00134

Gnomad AMR exome

AF:

0.0000768

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000373

Gnomad SAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.000518

Gnomad NFE exome

AF:

0.000342

Gnomad OTH exome

AF:

0.000526

GnomAD4 exome

AF:

0.000277

AC:

354

AN:

1278934

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

196

AN XY:

630076

show subpopulations

Gnomad4 AFR exome

AF:

0.000273

Gnomad4 AMR exome

AF:

0.0000781

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000109

Gnomad4 SAS exome

AF:

0.00157

Gnomad4 FIN exome

AF:

0.000355

Gnomad4 NFE exome

AF:

0.000207

Gnomad4 OTH exome

AF:

0.000151

GnomAD4 genome

AF:

0.000258

AC:

AN:

151156

Hom.:

Cov.:

AF XY:

0.000244

AC XY:

AN XY:

73860

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00167

Gnomad4 FIN

AF:

0.000290

Gnomad4 NFE

AF:

0.000192

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 28, 2022

This variant, c.61_63dup, results in the insertion of 1 amino acid(s) of the EIF2AK3 protein (p.Leu21dup), 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. This variant has not been reported in the literature in individuals affected with EIF2AK3-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

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