chr2-88575373-C-A

Variant names:

• chr2-88575373-C-A
• rs1805165
• NM_004836.7:c.2110G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004836.7(EIF2AK3):​c.2110G>T​(p.Ala704Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,613,760 control chromosomes in the GnomAD database, including 421,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A704V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.77 (45971 hom., cov: 32)
  • Exomes 𝑓: 0.71 (375836 hom.)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.73
• Publications: 63 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5892735E-7).
• BP6: Variant 2-88575373-C-A is Benign according to our data. Variant chr2-88575373-C-A is described in ClinVar as Benign. ClinVar VariationId is 128986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	NM_004836.7	MANE Select	c.2110G>T	p.Ala704Ser	missense	Exon 13 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.1657G>T	p.Ala553Ser	missense	Exon 13 of 17	NP_001300844.1
	EIF2AK3-AS1	NR_110236.1		n.1510C>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.2110G>T	p.Ala704Ser	missense	Exon 13 of 17	ENSP00000307235.3
	ENSG00000225420	ENST00000413234.1	TSL:1	n.1510C>A		non_coding_transcript_exon	Exon 3 of 3
	EIF2AK3	ENST00000415570.1	TSL:1	n.1779G>T		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116690 AN: 151990 Hom.: 45919 Cov.: 32

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.752

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.724

GnomAD2 exomes AF: 0.698 AC: 175097 AN: 251010 AF XY: 0.692

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.777

Gnomad EAS exome AF: 0.504

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.694

GnomAD4 exome AF: 0.714 AC: 1044020 AN: 1461652 Hom.: 375836 Cov.: 67 AF XY: 0.712 AC XY: 517684 AN XY: 727118

African (AFR) AF: 0.953 AC: 31906 AN: 33478

American (AMR) AF: 0.678 AC: 30313 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 20134 AN: 26136

East Asian (EAS) AF: 0.548 AC: 21763 AN: 39694

South Asian (SAS) AF: 0.620 AC: 53490 AN: 86258

European-Finnish (FIN) AF: 0.657 AC: 35008 AN: 53248

Middle Eastern (MID) AF: 0.744 AC: 4292 AN: 5766

European-Non Finnish (NFE) AF: 0.723 AC: 803473 AN: 1111956

Other (OTH) AF: 0.723 AC: 43641 AN: 60396

GnomAD4 genome AF: 0.768 AC: 116797 AN: 152108 Hom.: 45971 Cov.: 32 AF XY: 0.759 AC XY: 56399 AN XY: 74340

African (AFR) AF: 0.945 AC: 39238 AN: 41540

American (AMR) AF: 0.682 AC: 10401 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2721 AN: 3472

East Asian (EAS) AF: 0.526 AC: 2713 AN: 5156

South Asian (SAS) AF: 0.616 AC: 2971 AN: 4826

European-Finnish (FIN) AF: 0.653 AC: 6890 AN: 10548

Middle Eastern (MID) AF: 0.747 AC: 218 AN: 292

European-Non Finnish (NFE) AF: 0.728 AC: 49510 AN: 68000

Other (OTH) AF: 0.722 AC: 1523 AN: 2110

Alfa AF: 0.736 Hom.: 161734

Bravo AF: 0.780

TwinsUK AF: 0.716 AC: 2654

ALSPAC AF: 0.719 AC: 2771

ESP6500AA AF: 0.942 AC: 4150

ESP6500EA AF: 0.730 AC: 6277

ExAC AF: 0.702 AC: 85213

Asia WGS AF: 0.630 AC: 2194 AN: 3478

EpiCase AF: 0.736

EpiControl AF: 0.731

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	3	Wolcott-Rallison dysplasia (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.067	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.090	N
PhyloP100		2.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.099
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.034
MPC		0.31
ClinPred		0.0043	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.20
Mutation Taster		=98/2	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: rs1805165; hg19: chr2-88874891; COSMIC: COSV57547863; COSMIC: COSV57547863;