rs13045

Variant names:

• chr2-88595605-T-A
• rs13045
• NM_004836.7:c.497A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-88595605-T-A
• chr2-88595605-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004836.7(EIF2AK3):​c.497A>T​(p.Gln166Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q166R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• Publications: 54 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21324241).

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.497A>T	p.Gln166Leu	missense	Exon 3 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.44A>T	p.Gln15Leu	missense	Exon 3 of 17	NP_001300844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.497A>T	p.Gln166Leu	missense	Exon 3 of 17	ENSP00000307235.3
	EIF2AK3	ENST00000415570.1	TSL:1	n.166A>T		non_coding_transcript_exon	Exon 2 of 16
	EIF2AK3	ENST00000682892.1		c.44A>T	p.Gln15Leu	missense	Exon 4 of 18	ENSP00000507214.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 139115

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.25
Eigen_PC	Benign	0.0091
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.32
MutPred		0.49		Gain of sheet (P = 0.0101)
MVP		0.82
MPC		0.33
ClinPred		0.58	D
GERP RS		6.2
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.75
Mutation Taster		=60/40	polymorphism

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: rs13045; hg19: chr2-88895123;