2-88627211-CCAGCAGCAGCAG-CCAGCAGCAG

Position:

• chr2-88627211-CCAGCAGCAGCAG-CCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004836.7(EIF2AK3):​c.61_63delCTG​(p.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 0.668 in 1,420,252 control chromosomes in the GnomAD database, including 292,822 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (44865 hom., cov: 0)
  • Exomes 𝑓: 0.66 (247957 hom.)
• Consequence: EIF2AK3 NM_004836.7 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.81

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-88627211-CCAG-C is Benign according to our data. Variant chr2-88627211-CCAG-C is described in ClinVar as [Benign]. Clinvar id is 193295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-88627211-CCAG-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK3	NM_004836.7	c.61_63delCTG	p.Leu21del	conservative_inframe_deletion	1/17	ENST00000303236.9	NP_004827.4
EIF2AK3	XM_047446430.1	c.61_63delCTG	p.Leu21del	conservative_inframe_deletion	1/12		XP_047302386.1
EIF2AK3	XM_047446428.1	c.17+475_17+477delCTG		intron_variant			XP_047302384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.61_63delCTG	p.Leu21del	conservative_inframe_deletion	1/17	1	NM_004836.7	ENSP00000307235.3
EIF2AK3	ENST00000682892.1	c.-145-13361_-145-13359delCTG		intron_variant				ENSP00000507214.1
EIF2AK3	ENST00000652099.1	n.58_60delCTG		non_coding_transcript_exon_variant	1/18			ENSP00000498211.1
EIF2AK3	ENST00000652423.1	n.61_63delCTG		non_coding_transcript_exon_variant	1/4			ENSP00000498948.1

Frequencies

GnomAD3 genomes AF: 0.767 AC: 115735 AN: 150958 Hom.: 44810 Cov.: 0

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.825

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.558

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.746

GnomAD3 exomes AF: 0.709 AC: 46235 AN: 65220 Hom.: 15631 AF XY: 0.694 AC XY: 25884 AN XY: 37308

Gnomad AFR exome AF: 0.843

Gnomad AMR exome AF: 0.824

Gnomad ASJ exome AF: 0.616

Gnomad EAS exome AF: 0.791

Gnomad SAS exome AF: 0.641

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.656 AC: 833124 AN: 1269182 Hom.: 247957 AF XY: 0.652 AC XY: 407426 AN XY: 624626

Gnomad4 AFR exome AF: 0.782

Gnomad4 AMR exome AF: 0.730

Gnomad4 ASJ exome AF: 0.579

Gnomad4 EAS exome AF: 0.677

Gnomad4 SAS exome AF: 0.597

Gnomad4 FIN exome AF: 0.706

Gnomad4 NFE exome AF: 0.656

Gnomad4 OTH exome AF: 0.648

GnomAD4 genome AF: 0.767 AC: 115852 AN: 151070 Hom.: 44865 Cov.: 0 AF XY: 0.771 AC XY: 56895 AN XY: 73814

Gnomad4 AFR AF: 0.871

Gnomad4 AMR AF: 0.789

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.825

Gnomad4 SAS AF: 0.670

Gnomad4 FIN AF: 0.799

Gnomad4 NFE AF: 0.707

Gnomad4 OTH AF: 0.750

Bravo AF: 0.774

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wolcott-Rallison dysplasia Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1805190; hg19: chr2-88926729;