rs377410593

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-37107531-GA-G
• chr2-37107531-GA-GAA
• chr2-37107531-GA-GAAAAA
• chr2-37107531-GA-GAAAAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001135651.3(EIF2AK2):​c.1480-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,584,502 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: EIF2AK2 NM_001135651.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -6 ACMG points.

• BP6: Variant 2-37107531-GA-G is Benign according to our data. Variant chr2-37107531-GA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2417484.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 11 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.1480-5delT		splice_region intron	N/A	NP_001129123.1	P19525-1
	EIF2AK2	NM_002759.4		c.1480-5delT		splice_region intron	N/A	NP_002750.1	P19525-1
	EIF2AK2	NM_001135652.2		c.1357-5delT		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.1480-5delT		splice_region intron	N/A	ENSP00000233057.4	P19525-1
	EIF2AK2	ENST00000405334.5	TSL:1	c.1357-5delT		splice_region intron	N/A	ENSP00000385014.1	P19525-2
	EIF2AK2	ENST00000395127.6	TSL:5	c.1480-5delT		splice_region intron	N/A	ENSP00000378559.2	P19525-1

Frequencies

GnomAD3 genomes AF: 0.0000732 AC: 11 AN: 150312 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000125 AC: 27 AN: 215620 AF XY: 0.0000935

Gnomad AFR exome AF: 0.000346

Gnomad AMR exome AF: 0.000112

Gnomad ASJ exome AF: 0.000236

Gnomad EAS exome AF: 0.000128

Gnomad FIN exome AF: 0.000110

Gnomad NFE exome AF: 0.0000787

Gnomad OTH exome AF: 0.000401

GnomAD4 exome AF: 0.0000321 AC: 46 AN: 1434072 Hom.: 0 Cov.: 31 AF XY: 0.0000294 AC XY: 21 AN XY: 713570

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

African (AFR) AF: 0.000157 AC: 5 AN: 31854

American (AMR) AF: 0.000176 AC: 7 AN: 39806

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25334

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39244

South Asian (SAS) AF: 0.0000607 AC: 5 AN: 82318

European-Finnish (FIN) AF: 0.000117 AC: 6 AN: 51432

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5536

European-Non Finnish (NFE) AF: 0.0000155 AC: 17 AN: 1099556

Other (OTH) AF: 0.0000509 AC: 3 AN: 58992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000111022), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000731 AC: 11 AN: 150430 Hom.: 0 Cov.: 32 AF XY: 0.0000817 AC XY: 6 AN XY: 73430

African (AFR) AF: 0.000146 AC: 6 AN: 41096

American (AMR) AF: 0.0000663 AC: 1 AN: 15086

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

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10124

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

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67488

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: COSV51794818;