rs55791823

Variant names:

• chr2-88583496-T-A
• rs55791823
• NM_004836.7:c.1697A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-88583496-T-A
• chr2-88583496-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004836.7(EIF2AK3):​c.1697A>T​(p.Asp566Val) variant causes a missense change. The variant allele was found at a frequency of 0.00415 in 1,613,262 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D566G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (20 hom.)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 7.12
• Publications: 11 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009609789).
• BP6: Variant 2-88583496-T-A is Benign according to our data. Variant chr2-88583496-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337412.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00258 (393/152294) while in subpopulation NFE AF = 0.00453 (308/68016). AF 95% confidence interval is 0.00411. There are 0 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

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.1697A>T	p.Asp566Val	missense	Exon 10 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.1244A>T	p.Asp415Val	missense	Exon 10 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.1697A>T	p.Asp566Val	missense	Exon 10 of 17	ENSP00000307235.3
	EIF2AK3	ENST00000415570.1	TSL:1	n.1366A>T		non_coding_transcript_exon	Exon 9 of 16
	EIF2AK3	ENST00000682892.1		c.1244A>T	p.Asp415Val	missense	Exon 11 of 18	ENSP00000507214.1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00260 AC: 653 AN: 250846 AF XY: 0.00249

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.00490

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00432 AC: 6307 AN: 1460968 Hom.: 20 Cov.: 31 AF XY: 0.00415 AC XY: 3015 AN XY: 726836

African (AFR) AF: 0.000747 AC: 25 AN: 33452

American (AMR) AF: 0.000358 AC: 16 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00331 AC: 176 AN: 53118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00533 AC: 5924 AN: 1111658

Other (OTH) AF: 0.00229 AC: 138 AN: 60358

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74492

African (AFR) AF: 0.00108 AC: 45 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00246

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00264 AC: 321

EpiCase AF: 0.00376

EpiControl AF: 0.00415

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	3	1	Wolcott-Rallison dysplasia (4)
-	1	-	Connective tissue disorder (1)
-	-	1	EIF2AK3-related disorder (1)
-	-	1	Monogenic diabetes (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.015	D
Sift4G	Benign	0.29	T
Polyphen		0.99	D
Vest4		0.52
MVP		0.91
MPC		0.52
ClinPred		0.017	T
GERP RS		5.7
Varity_R		0.22
gMVP		0.67
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs55791823; hg19: chr2-88883014;