15-39976797-GGAC-GGACGACGAC

Variant names:

• chr15-39976797-G-GGACGAC
• rs377237751
• NM_001013703.4:c.2208_2213dupCGACGA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 1P and 17B. PP3 BP3 BP6_Very_Strong BA1

The NM_001013703.4(EIF2AK4):​c.2208_2213dupCGACGA​(p.Asp736_Asp737dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,574,298 control chromosomes in the GnomAD database, including 10,196 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (734 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9462 hom.)
• Consequence: EIF2AK4 NM_001013703.4 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.78
• Publications: 11 publications found

Genes affected

EIF2AK4 (HGNC:19687): (eukaryotic translation initiation factor 2 alpha kinase 4) This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by binding uncharged transfer RNAs. It may also be activated by glucose deprivation and viral infection. Mutations in this gene have been found in individuals suffering from autosomal recessive pulmonary venoocclusive-disease-2. [provided by RefSeq, Mar 2014]

EIF2AK4 Gene-Disease associations (from GenCC):

• pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary venoocclusive disease 2

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary venoocclusive disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP3: Nonframeshift variant in repetitive region in NM_001013703.4
• BP6: Variant 15-39976797-G-GGACGAC is Benign according to our data. Variant chr15-39976797-G-GGACGAC is described in ClinVar as Benign. ClinVar VariationId is 402821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013703.4. 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
	EIF2AK4	NM_001013703.4	MANE Select	c.2208_2213dupCGACGA	p.Asp736_Asp737dup	disruptive_inframe_insertion	Exon 12 of 39	NP_001013725.2	Q9P2K8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	ENST00000263791.10	TSL:2 MANE Select	c.2208_2213dupCGACGA	p.Asp736_Asp737dup	disruptive_inframe_insertion	Exon 12 of 39	ENSP00000263791.5	Q9P2K8-1
	EIF2AK4	ENST00000917949.1		c.2250_2255dupCGACGA	p.Asp750_Asp751dup	disruptive_inframe_insertion	Exon 13 of 40	ENSP00000588008.1
	EIF2AK4	ENST00000917947.1		c.2208_2213dupCGACGA	p.Asp736_Asp737dup	disruptive_inframe_insertion	Exon 12 of 38	ENSP00000588006.1

Frequencies

GnomAD3 genomes AF: 0.0851 AC: 12947 AN: 152202 Hom.: 734 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.0848

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0965

GnomAD2 exomes AF: 0.0989 AC: 20279 AN: 205028 AF XY: 0.107

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.0552

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.0687

Gnomad FIN exome AF: 0.0715

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.109 AC: 155655 AN: 1421982 Hom.: 9462 Cov.: 31 AF XY: 0.113 AC XY: 79605 AN XY: 705002

African (AFR) AF: 0.0217 AC: 667 AN: 30734

American (AMR) AF: 0.0598 AC: 2365 AN: 39544

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3340 AN: 24360

East Asian (EAS) AF: 0.0651 AC: 2443 AN: 37534

South Asian (SAS) AF: 0.206 AC: 16653 AN: 80658

European-Finnish (FIN) AF: 0.0769 AC: 3828 AN: 49806

Middle Eastern (MID) AF: 0.200 AC: 1131 AN: 5648

European-Non Finnish (NFE) AF: 0.109 AC: 118994 AN: 1094974

Other (OTH) AF: 0.106 AC: 6234 AN: 58724

GnomAD4 genome AF: 0.0850 AC: 12945 AN: 152316 Hom.: 734 Cov.: 32 AF XY: 0.0885 AC XY: 6591 AN XY: 74470

African (AFR) AF: 0.0253 AC: 1052 AN: 41590

American (AMR) AF: 0.0847 AC: 1297 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3472

East Asian (EAS) AF: 0.0635 AC: 329 AN: 5182

South Asian (SAS) AF: 0.225 AC: 1087 AN: 4830

European-Finnish (FIN) AF: 0.0840 AC: 892 AN: 10614

Middle Eastern (MID) AF: 0.238 AC: 69 AN: 290

European-Non Finnish (NFE) AF: 0.110 AC: 7458 AN: 68000

Other (OTH) AF: 0.0950 AC: 201 AN: 2116

Alfa AF: 0.0622 Hom.: 91

Asia WGS AF: 0.114 AC: 397 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Familial pulmonary capillary hemangiomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs377237751; hg19: chr15-40268998; COSMIC: COSV55464446; COSMIC: COSV55464446;