rs11684404

Variant names:

• chr2-88625104-T-C
• rs11684404
• NM_004836.7:c.308+1863A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004836.7(EIF2AK3):​c.308+1863A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,098 control chromosomes in the GnomAD database, including 7,481 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (7481 hom., cov: 32)
• Consequence: EIF2AK3 NM_004836.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400
• Publications: 51 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7	c.308+1863A>G		intron_variant	Intron 1 of 16	ENST00000303236.9	NP_004827.4
EIF2AK3	XM_047446428.1	c.17+2585A>G		intron_variant	Intron 1 of 16		XP_047302384.1
EIF2AK3	XM_047446430.1	c.308+1863A>G		intron_variant	Intron 1 of 11		XP_047302386.1
EIF2AK3	NM_001313915.2	c.-504A>G		upstream_gene_variant			NP_001300844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.308+1863A>G		intron_variant	Intron 1 of 16	1	NM_004836.7	ENSP00000307235.3

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43763 AN: 151980 Hom.: 7471 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.320

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

GnomAD4 genome AF: 0.288 AC: 43786 AN: 152098 Hom.: 7481 Cov.: 32 AF XY: 0.296 AC XY: 22026 AN XY: 74338

African (AFR) AF: 0.105 AC: 4341 AN: 41514

American (AMR) AF: 0.375 AC: 5732 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 935 AN: 3472

East Asian (EAS) AF: 0.509 AC: 2631 AN: 5166

South Asian (SAS) AF: 0.473 AC: 2281 AN: 4818

European-Finnish (FIN) AF: 0.408 AC: 4313 AN: 10572

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22465 AN: 67960

Other (OTH) AF: 0.323 AC: 682 AN: 2114

Alfa AF: 0.311 Hom.: 14897

Bravo AF: 0.275

Asia WGS AF: 0.434 AC: 1508 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.34
PhyloP100		-0.0040
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11684404; hg19: chr2-88924622;