2-37107531-GA-GAA

Variant names:

• chr2-37107531-G-GA
• rs377410593
• NM_001135651.3:c.1480-5dupT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001135651.3(EIF2AK2):​c.1480-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,580,578 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: EIF2AK2 NM_001135651.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P, Illumina
• 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: Likely_benign. The variant received -4 ACMG points.

• 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.1480-5dupT		splice_region intron	N/A	NP_001129123.1	P19525-1
	EIF2AK2	NM_002759.4		c.1480-5dupT		splice_region intron	N/A	NP_002750.1	P19525-1
	EIF2AK2	NM_001135652.2		c.1357-5dupT		splice_region intron	N/A	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.1480-5_1480-4insT		splice_region intron	N/A	ENSP00000233057.4	P19525-1
	EIF2AK2	ENST00000405334.5	TSL:1	c.1357-5_1357-4insT		splice_region intron	N/A	ENSP00000385014.1	P19525-2
	EIF2AK2	ENST00000395127.6	TSL:5	c.1480-5_1480-4insT		splice_region intron	N/A	ENSP00000378559.2	P19525-1

Frequencies

GnomAD3 genomes AF: 0.0000532 AC: 8 AN: 150310 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.0000988

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000450 AC: 97 AN: 215620 AF XY: 0.000434

Gnomad AFR exome AF: 0.000208

Gnomad AMR exome AF: 0.000633

Gnomad ASJ exome AF: 0.000354

Gnomad EAS exome AF: 0.000960

Gnomad FIN exome AF: 0.000767

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.000401

GnomAD4 exome AF: 0.000212 AC: 303 AN: 1430268 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 154 AN XY: 711758

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000315 AC: 10 AN: 31774

American (AMR) AF: 0.000605 AC: 24 AN: 39644

Ashkenazi Jewish (ASJ) AF: 0.000198 AC: 5 AN: 25262

East Asian (EAS) AF: 0.000357 AC: 14 AN: 39166

South Asian (SAS) AF: 0.000768 AC: 63 AN: 82022

European-Finnish (FIN) AF: 0.000448 AC: 23 AN: 51290

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5526

European-Non Finnish (NFE) AF: 0.000137 AC: 150 AN: 1096762

Other (OTH) AF: 0.000221 AC: 13 AN: 58822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000532 AC: 8 AN: 150310 Hom.: 0 Cov.: 32 AF XY: 0.0000409 AC XY: 3 AN XY: 73298

African (AFR) AF: 0.000122 AC: 5 AN: 40976

American (AMR) AF: 0.0000664 AC: 1 AN: 15066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4740

European-Finnish (FIN) AF: 0.0000988 AC: 1 AN: 10122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67496

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00225 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

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: rs377410593; hg19: chr2-37334674; COSMIC: COSV99240892;