2-88583430-C-T

Variant names:

• chr2-88583430-C-T
• rs121908569
• NM_004836.7:c.1763G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004836.7(EIF2AK3):​c.1763G>A​(p.Arg588Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,451,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R588R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.82
• Publications: 5 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: Ambry Genetics, Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-88583430-C-T is Pathogenic according to our data. Variant chr2-88583430-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5875.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1763G>A	p.Arg588Gln	missense splice_region	Exon 10 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.1310G>A	p.Arg437Gln	missense splice_region	Exon 10 of 17	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.1763G>A	p.Arg588Gln	missense splice_region	Exon 10 of 17	ENSP00000307235.3	Q9NZJ5
	EIF2AK3	ENST00000415570.1	TSL:1	n.1432G>A		splice_region non_coding_transcript_exon	Exon 9 of 16
	EIF2AK3	ENST00000682892.1		c.1310G>A	p.Arg437Gln	missense splice_region	Exon 11 of 18	ENSP00000507214.1	A0A804HIT4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451472 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 722762

African (AFR) AF: 0.00 AC: 0 AN: 33224

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39488

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103312

Other (OTH) AF: 0.00 AC: 0 AN: 60028

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Wolcott-Rallison dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.78		Loss of phosphorylation at T591 (P = 0.1065)
MVP		0.87
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.78
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 0

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

Other links and lift over

dbSNP: rs121908569; hg19: chr2-88882948; COSMIC: COSV57548278; COSMIC: COSV57548278;