2-88627211-CCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr2-88627211-C-CCAGCAGCAGCAG
• rs1805190
• NM_004836.7:c.52_63dupCTGCTGCTGCTG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_004836.7(EIF2AK3):​c.52_63dupCTGCTGCTGCTG​(p.Leu18_Leu21dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.853
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004836.7

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.52_63dupCTGCTGCTGCTG	p.Leu18_Leu21dup	conservative_inframe_insertion	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.52_63dupCTGCTGCTGCTG	p.Leu18_Leu21dup	conservative_inframe_insertion	Exon 1 of 17	ENSP00000307235.3
	EIF2AK3	ENST00000682892.1		c.-145-13370_-145-13359dupCTGCTGCTGCTG		intron	N/A	ENSP00000507214.1
	EIF2AK3	ENST00000652099.1		n.49_60dupCTGCTGCTGCTG		non_coding_transcript_exon	Exon 1 of 18	ENSP00000498211.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1278938 Hom.: 0 Cov.: 0 AF XY: 0.00000159 AC XY: 1 AN XY: 630080

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

African (AFR) AF: 0.00 AC: 0 AN: 25618

American (AMR) AF: 0.00 AC: 0 AN: 25616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22646

East Asian (EAS) AF: 0.00 AC: 0 AN: 27398

South Asian (SAS) AF: 0.0000142 AC: 1 AN: 70544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3816

European-Non Finnish (NFE) AF: 9.81e-7 AC: 1 AN: 1019350

Other (OTH) AF: 0.00 AC: 0 AN: 52998

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85

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;