rs4648186

Variant names:

• chr2-37139964-G-A
• rs4648186
• NM_001135651.3:c.390-207C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-37139964-G-A
• chr2-37139964-G-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.390-207C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,120 control chromosomes in the GnomAD database, including 992 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 0.11 (992 hom., cov: 32)
• Consequence: EIF2AK2 NM_001135651.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.554
• Publications: 13 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK2	NM_001135651.3	c.390-207C>T		intron_variant	Intron 5 of 16	ENST00000233057.9	NP_001129123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK2	ENST00000233057.9	c.390-207C>T		intron_variant	Intron 5 of 16	2	NM_001135651.3	ENSP00000233057.4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16193 AN: 152004 Hom.: 993 Cov.: 32

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0749

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.00557

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.106 AC: 16195 AN: 152120 Hom.: 992 Cov.: 32 AF XY: 0.105 AC XY: 7837 AN XY: 74376

African (AFR) AF: 0.0653 AC: 2710 AN: 41488

American (AMR) AF: 0.0748 AC: 1143 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3470

East Asian (EAS) AF: 0.00558 AC: 29 AN: 5194

South Asian (SAS) AF: 0.144 AC: 693 AN: 4812

European-Finnish (FIN) AF: 0.133 AC: 1408 AN: 10552

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9425 AN: 68004

Other (OTH) AF: 0.119 AC: 250 AN: 2108

Alfa AF: 0.122 Hom.: 2283

Bravo AF: 0.0981

Asia WGS AF: 0.0580 AC: 203 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.9
DANN	Benign	0.36
PhyloP100		0.55
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: rs4648186; hg19: chr2-37367107;