2-88627211-CCAGCAGCAGCAG-CCAGCAG

Variant names:

• chr2-88627211-CCAGCAG-C
• rs1805190
• NM_004836.7:c.58_63delCTGCTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_004836.7(EIF2AK3):​c.58_63delCTGCTG​(p.Leu20_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 0.00211 in 1,289,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. L20L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 conservative_inframe_deletion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.98
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0124) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP3: Nonframeshift variant in repetitive region in NM_004836.7
• BP6: Variant 2-88627211-CCAGCAG-C is Benign according to our data. Variant chr2-88627211-CCAGCAG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3037443.Status of the report is no_assertion_criteria_provided, 0 stars.

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.58_63delCTGCTG	p.Leu20_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.58_63delCTGCTG	p.Leu20_Leu21del	conservative_inframe_deletion	Exon 1 of 17	ENSP00000307235.3
	EIF2AK3	ENST00000682892.1		c.-145-13364_-145-13359delCTGCTG		intron	N/A	ENSP00000507214.1
	EIF2AK3	ENST00000652099.1		n.55_60delCTGCTG		non_coding_transcript_exon	Exon 1 of 18	ENSP00000498211.1

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 150804 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000243

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: 0.000195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00647 AC: 422 AN: 65220 AF XY: 0.00675

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.00791

Gnomad ASJ exome AF: 0.00326

Gnomad EAS exome AF: 0.0138

Gnomad FIN exome AF: 0.00751

Gnomad NFE exome AF: 0.00628

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00239 AC: 2718 AN: 1138122 Hom.: 0 AF XY: 0.00267 AC XY: 1497 AN XY: 559882

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00320 AC: 68 AN: 21262

American (AMR) AF: 0.0137 AC: 290 AN: 21202

Ashkenazi Jewish (ASJ) AF: 0.00362 AC: 74 AN: 20436

East Asian (EAS) AF: 0.00187 AC: 44 AN: 23592

South Asian (SAS) AF: 0.00694 AC: 428 AN: 61696

European-Finnish (FIN) AF: 0.00579 AC: 149 AN: 25740

Middle Eastern (MID) AF: 0.00227 AC: 8 AN: 3518

European-Non Finnish (NFE) AF: 0.00168 AC: 1532 AN: 913778

Other (OTH) AF: 0.00267 AC: 125 AN: 46898

⚠️ 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.

GnomAD4 genome AF: 0.0000464 AC: 7 AN: 150916 Hom.: 0 Cov.: 0 AF XY: 0.0000678 AC XY: 5 AN XY: 73726

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41300

American (AMR) AF: 0.00 AC: 0 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.000195 AC: 2 AN: 10252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000592 AC: 4 AN: 67544

Other (OTH) AF: 0.00 AC: 0 AN: 2098

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1872

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EIF2AK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=143/57	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1805190; hg19: chr2-88926729;