2-88627211-CCAGCAGCAGCAG-CCAGCAGCAG

Variant names:

• chr2-88627211-CCAG-C
• rs1805190
• NM_004836.7:c.61_63delCTG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely 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
• 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 syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004836.7
• BP6: Variant 2-88627211-CCAG-C is Benign according to our data. Variant chr2-88627211-CCAG-C is described in ClinVar as Benign. ClinVar VariationId is 193295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

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.61_63delCTG	p.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.61_63delCTG	p.Leu21del	conservative_inframe_deletion	Exon 1 of 17	ENSP00000307235.3
	EIF2AK3	ENST00000682892.1		c.-145-13361_-145-13359delCTG		intron	N/A	ENSP00000507214.1
	EIF2AK3	ENST00000652099.1		n.58_60delCTG		non_coding_transcript_exon	Exon 1 of 18	ENSP00000498211.1

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

GnomAD2 exomes AF: 0.709 AC: 46235 AN: 65220 AF XY: 0.694

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 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

African (AFR) AF: 0.782 AC: 20001 AN: 25568

American (AMR) AF: 0.730 AC: 18619 AN: 25506

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 12910 AN: 22278

East Asian (EAS) AF: 0.677 AC: 18417 AN: 27216

South Asian (SAS) AF: 0.597 AC: 41153 AN: 68888

European-Finnish (FIN) AF: 0.706 AC: 21729 AN: 30784

Middle Eastern (MID) AF: 0.547 AC: 2053 AN: 3750

European-Non Finnish (NFE) AF: 0.656 AC: 664209 AN: 1012662

Other (OTH) AF: 0.648 AC: 34033 AN: 52530

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

African (AFR) AF: 0.871 AC: 35972 AN: 41318

American (AMR) AF: 0.789 AC: 11994 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2137 AN: 3452

East Asian (EAS) AF: 0.825 AC: 4185 AN: 5072

South Asian (SAS) AF: 0.670 AC: 3217 AN: 4800

European-Finnish (FIN) AF: 0.799 AC: 8254 AN: 10332

Middle Eastern (MID) AF: 0.555 AC: 161 AN: 290

European-Non Finnish (NFE) AF: 0.707 AC: 47788 AN: 67584

Other (OTH) AF: 0.750 AC: 1576 AN: 2102

Alfa AF: 0.657 Hom.: 1872

Bravo AF: 0.774

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Wolcott-Rallison dysplasia (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=75/25	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805190; hg19: chr2-88926729; COSMIC: COSV57547957; COSMIC: COSV57547957;