2-88557376-G-A

Variant names:

• chr2-88557376-G-A
• rs551581209
• NM_004836.7:c.*360C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_004836.7(EIF2AK3):​c.*360C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 242,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.569
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp, G2P

ENSG00000225420 (HGNC:58177):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000118 (18/151944) while in subpopulation SAS AF = 0.000208 (1/4808). AF 95% confidence interval is 0.000124. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. 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.*360C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000303236.9	NP_004827.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.*360C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_004836.7	ENSP00000307235.3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151944 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000992 AC: 9 AN: 90690 Hom.: 0 Cov.: 0 AF XY: 0.0000632 AC XY: 3 AN XY: 47496

African (AFR) AF: 0.00 AC: 0 AN: 3322

American (AMR) AF: 0.00 AC: 0 AN: 4736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5450

South Asian (SAS) AF: 0.00 AC: 0 AN: 10906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 356

European-Non Finnish (NFE) AF: 0.000166 AC: 9 AN: 54234

Other (OTH) AF: 0.00 AC: 0 AN: 5020

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151944 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74196

African (AFR) AF: 0.0000484 AC: 2 AN: 41358

American (AMR) AF: 0.0000656 AC: 1 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wolcott-Rallison dysplasia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.64
DANN	Benign	0.18
PhyloP100		0.57

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: rs551581209; hg19: chr2-88856894;