2-88627211-CCAGCAGCAGCAG-CCAGCAGCAGCAGCAG

Variant names:

• chr2-88627211-C-CCAG
• rs1805190
• NM_004836.7:c.61_63dupCTG

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_004836.7(EIF2AK3):​c.61_63dupCTG​(p.Leu21dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.853

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 Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000258 (39/151156) while in subpopulation SAS AF= 0.00167 (8/4804). AF 95% confidence interval is 0.000828. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7	c.61_63dupCTG	p.Leu21dup	conservative_inframe_insertion	Exon 1 of 17	ENST00000303236.9	NP_004827.4
EIF2AK3	XM_047446430.1	c.61_63dupCTG	p.Leu21dup	conservative_inframe_insertion	Exon 1 of 12		XP_047302386.1
EIF2AK3	XM_047446428.1	c.17+475_17+477dupCTG		intron_variant	Intron 1 of 16		XP_047302384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.61_63dupCTG	p.Leu21dup	conservative_inframe_insertion	Exon 1 of 17	1	NM_004836.7	ENSP00000307235.3
EIF2AK3	ENST00000682892.1	c.-145-13361_-145-13359dupCTG		intron_variant	Intron 2 of 17			ENSP00000507214.1
EIF2AK3	ENST00000652099.1	n.58_60dupCTG		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000498211.1
EIF2AK3	ENST00000652423.1	n.61_63dupCTG		non_coding_transcript_exon_variant	Exon 1 of 4			ENSP00000498948.1

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 39 AN: 151044 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000290

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000613 AC: 40 AN: 65220 Hom.: 0 AF XY: 0.000777 AC XY: 29 AN XY: 37308

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.0000768

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000373

Gnomad SAS exome AF: 0.00185

Gnomad FIN exome AF: 0.000518

Gnomad NFE exome AF: 0.000342

Gnomad OTH exome AF: 0.000526

GnomAD4 exome AF: 0.000277 AC: 354 AN: 1278934 Hom.: 0 Cov.: 0 AF XY: 0.000311 AC XY: 196 AN XY: 630076

Gnomad4 AFR exome AF: 0.000273

Gnomad4 AMR exome AF: 0.0000781

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.000355

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome AF: 0.000258 AC: 39 AN: 151156 Hom.: 0 Cov.: 0 AF XY: 0.000244 AC XY: 18 AN XY: 73860

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.000290

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.61_63dup, results in the insertion of 1 amino acid(s) of the EIF2AK3 protein (p.Leu21dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with EIF2AK3-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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;