2-88627211-CCAGCAGCAGCAG-CCAGCAG

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

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).

• 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

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 3037443.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-88627211-CCAGCAG-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00239 (2718/1138122) while in subpopulation AMR AF= 0.0137 (290/21202). AF 95% confidence interval is 0.0124. There are 0 homozygotes in gnomad4_exome. There are 1497 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7	c.58_63delCTGCTG	p.Leu20_Leu21del	conservative_inframe_deletion	Exon 1 of 17	ENST00000303236.9	NP_004827.4
EIF2AK3	XM_047446430.1	c.58_63delCTGCTG	p.Leu20_Leu21del	conservative_inframe_deletion	Exon 1 of 12		XP_047302386.1
EIF2AK3	XM_047446428.1	c.17+472_17+477delCTGCTG		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.58_63delCTGCTG	p.Leu20_Leu21del	conservative_inframe_deletion	Exon 1 of 17	1	NM_004836.7	ENSP00000307235.3
EIF2AK3	ENST00000682892.1	c.-145-13364_-145-13359delCTGCTG		intron_variant	Intron 2 of 17			ENSP00000507214.1
EIF2AK3	ENST00000652099.1	n.55_60delCTGCTG		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000498211.1
EIF2AK3	ENST00000652423.1	n.58_63delCTGCTG		non_coding_transcript_exon_variant	Exon 1 of 4			ENSP00000498948.1

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

GnomAD3 exomes AF: 0.00647 AC: 422 AN: 65220 Hom.: 0 AF XY: 0.00675 AC XY: 252 AN XY: 37308

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 SAS exome AF: 0.00525

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

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.0137

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.00187

Gnomad4 SAS exome AF: 0.00694

Gnomad4 FIN exome AF: 0.00579

Gnomad4 NFE exome AF: 0.00168

Gnomad4 OTH exome AF: 0.00267

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

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000195

Gnomad4 NFE AF: 0.0000592

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

EIF2AK3-related disorder Benign:1

Apr 14, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;