Genetic Variant EIF2AK3:p.Lys1038Lys (chr2-88558953-T-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_004836.7(EIF2AK3):c.3114A>G(p.Lys1038Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EIF2AK3
NM_004836.7 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.404

Publications

0 publications found

Variant links:

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)

EIF2AK3 links:

EIF2AK3-AS1 (HGNC:58177):

EIF2AK3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP7

Synonymous conserved (PhyloP=-0.404 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2AK3	NM_004836.7	MANE Select	c.3114A>G	p.Lys1038Lys	synonymous	Exon 16 of 17	NP_004827.4
EIF2AK3	NM_001313915.2		c.2661A>G	p.Lys887Lys	synonymous	Exon 16 of 17	NP_001300844.1	A0A804HIT4
EIF2AK3-AS1	NR_110236.1		n.651-15561T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.3114A>G	p.Lys1038Lys	synonymous	Exon 16 of 17	ENSP00000307235.3	Q9NZJ5
EIF2AK3	ENST00000415570.1	TSL:1	n.2783A>G		non_coding_transcript_exon	Exon 15 of 16
EIF2AK3-AS1	ENST00000413234.1	TSL:1	n.651-15561T>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250256

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33136

American (AMR)

AF:

0.00

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.00

AC:

AN:

85888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098574

Other (OTH)

AF:

0.00

AC:

AN:

59866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.2

(source)

DANN

Benign

0.91

PhyloP100

-0.40

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over