2-88579640-TC-CG

Variant names:

• chr2-88579640-TC-CG
• NM_004836.7:c.1764-1_1764delGAinsCG
• EIF2AK3 p.589

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_004836.7(EIF2AK3):​c.1764-1_1764delGAinsCG​(p.589) variant causes a splice acceptor, splice region, synonymous, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, 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. R588R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK3 NM_004836.7 splice_acceptor, splice_region, synonymous, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03670546 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	NM_004836.7	MANE Select	c.1764-1_1764delGAinsCG	p.589	splice_acceptor splice_region synonymous intron	N/A	NP_004827.4
	EIF2AK3	NM_001313915.2		c.1311-1_1311delGAinsCG	p.438	splice_acceptor splice_region synonymous intron	N/A	NP_001300844.1	A0A804HIT4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.1764-1_1764delGAinsCG	p.589	splice_acceptor splice_region synonymous intron	N/A	ENSP00000307235.3	Q9NZJ5
	EIF2AK3	ENST00000415570.1	TSL:1	n.1433-1_1433delGAinsCG		splice_acceptor splice_region intron non_coding_transcript_exon	Exon 10 of 16
	EIF2AK3	ENST00000682892.1		c.1311-1_1311delGAinsCG	p.438	splice_acceptor splice_region synonymous intron	N/A	ENSP00000507214.1	A0A804HIT4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-88879158;