2-37156172-A-G

Variant names:

• chr2-37156172-A-G
• rs12712526
• NM_001135651.3:c.-184+736T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001135651.3(EIF2AK2):​c.-184+736T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 151,828 control chromosomes in the GnomAD database, including 16,272 homozygotes. 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: 𝑓 0.46 (16272 hom., cov: 30)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.436
• Publications: 8 publications found

Genes affected

EIF2AK2 (HGNC:9437): (eukaryotic translation initiation factor 2 alpha kinase 2) The protein encoded by this gene is a serine/threonine protein kinase that is activated by autophosphorylation after binding to dsRNA. The activated form of the encoded protein can phosphorylate translation initiation factor EIF2S1, which in turn inhibits protein synthesis. This protein is also activated by manganese ions and heparin. The encoded protein plays an important role in the innate immune response against multiple DNA and RNA viruses. [provided by RefSeq, Jul 2021]

EIF2AK2 Gene-Disease associations (from GenCC):

• leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Illumina, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• early-onset generalized limb-onset dystonia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dystonia 33

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK2	NM_001135651.3	c.-184+736T>C		intron_variant	Intron 1 of 16	ENST00000233057.9	NP_001129123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK2	ENST00000233057.9	c.-184+736T>C		intron_variant	Intron 1 of 16	2	NM_001135651.3	ENSP00000233057.4

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69134 AN: 151710 Hom.: 16270 Cov.: 30

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.491

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.456 AC: 69166 AN: 151828 Hom.: 16272 Cov.: 30 AF XY: 0.462 AC XY: 34260 AN XY: 74206

African (AFR) AF: 0.377 AC: 15596 AN: 41340

American (AMR) AF: 0.426 AC: 6505 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1895 AN: 3470

East Asian (EAS) AF: 0.772 AC: 3989 AN: 5168

South Asian (SAS) AF: 0.400 AC: 1928 AN: 4822

European-Finnish (FIN) AF: 0.544 AC: 5728 AN: 10522

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32018 AN: 67940

Other (OTH) AF: 0.493 AC: 1037 AN: 2102

Alfa AF: 0.466 Hom.: 63303

Bravo AF: 0.449

Asia WGS AF: 0.548 AC: 1905 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.2
DANN	Benign	0.78
PhyloP100		0.44
Mutation Taster		=100/0	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: rs12712526; hg19: chr2-37383315;