2-88627211-CCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAG

Variant names:

• chr2-88627211-C-CCAGCAG
• rs1805190
• NM_004836.7:c.58_63dupCTGCTG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_004836.7(EIF2AK3):​c.58_63dupCTGCTG​(p.Leu20_Leu21dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.853
• 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004836.7
• BP6: Variant 2-88627211-C-CCAGCAG is Benign according to our data. Variant chr2-88627211-C-CCAGCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1061835.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000132 (20/151044) while in subpopulation EAS AF = 0.000393 (2/5088). AF 95% confidence interval is 0.000125. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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_63dupCTGCTG	p.Leu20_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.58_63dupCTGCTG	p.Leu20_Leu21dup	conservative_inframe_insertion	Exon 1 of 17	ENSP00000307235.3
	EIF2AK3	ENST00000682892.1		c.-145-13364_-145-13359dupCTGCTG		intron	N/A	ENSP00000507214.1
	EIF2AK3	ENST00000652099.1		n.55_60dupCTGCTG		non_coding_transcript_exon	Exon 1 of 18	ENSP00000498211.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151044 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000199 AC: 13 AN: 65220 AF XY: 0.000241

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00224

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000206 AC: 263 AN: 1278938 Hom.: 0 Cov.: 0 AF XY: 0.000200 AC XY: 126 AN XY: 630080

African (AFR) AF: 0.000117 AC: 3 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: 0.000146 AC: 4 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: 0.000524 AC: 2 AN: 3816

European-Non Finnish (NFE) AF: 0.000243 AC: 248 AN: 1019350

Other (OTH) AF: 0.0000943 AC: 5 AN: 52998

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151044 Hom.: 0 Cov.: 0 AF XY: 0.000122 AC XY: 9 AN XY: 73738

African (AFR) AF: 0.0000970 AC: 4 AN: 41216

American (AMR) AF: 0.00 AC: 0 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.000393 AC: 2 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000207 AC: 14 AN: 67636

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.000400 Hom.: 1872

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Connective tissue disorder (1)
-	1	-	not provided (1)
-	1	-	Wolcott-Rallison dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85
Mutation Taster		=79/21	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;