NM_001135651.3:c.1416C>T

Variant names:

• chr2-37109257-G-A
• rs376530608
• NM_001135651.3:c.1416C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001135651.3(EIF2AK2):​c.1416C>T​(p.Tyr472Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: EIF2AK2 NM_001135651.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.176
• Publications: 1 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-37109257-G-A is Benign according to our data. Variant chr2-37109257-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2158809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.176 with no splicing effect.
• BS2: High AC in GnomAd4 at 8 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135651.3. 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
	EIF2AK2	NM_001135651.3	MANE Select	c.1416C>T	p.Tyr472Tyr	synonymous	Exon 15 of 17	NP_001129123.1	P19525-1
	EIF2AK2	NM_002759.4		c.1416C>T	p.Tyr472Tyr	synonymous	Exon 15 of 17	NP_002750.1	P19525-1
	EIF2AK2	NM_001135652.2		c.1293C>T	p.Tyr431Tyr	synonymous	Exon 12 of 14	NP_001129124.1	P19525-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK2	ENST00000233057.9	TSL:2 MANE Select	c.1416C>T	p.Tyr472Tyr	synonymous	Exon 15 of 17	ENSP00000233057.4	P19525-1
	EIF2AK2	ENST00000405334.5	TSL:1	c.1293C>T	p.Tyr431Tyr	synonymous	Exon 12 of 14	ENSP00000385014.1	P19525-2
	EIF2AK2	ENST00000395127.6	TSL:5	c.1416C>T	p.Tyr472Tyr	synonymous	Exon 15 of 17	ENSP00000378559.2	P19525-1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251352 AF XY: 0.000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461818 Hom.: 0 Cov.: 30 AF XY: 0.000160 AC XY: 116 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39684

South Asian (SAS) AF: 0.000788 AC: 68 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111982

Other (OTH) AF: 0.000149 AC: 9 AN: 60394

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74506

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000416

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.7
DANN	Benign	0.41
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376530608; hg19: chr2-37336400; COSMIC: COSV51794486;