rs2250402

Variant names:

• chr15-40030351-G-T
• rs2250402
• NM_001013703.4:c.4562-8G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-40030351-G-T
• chr15-40030351-G-A
• chr15-40030351-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001013703.4(EIF2AK4):​c.4562-8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.916 in 1,613,276 control chromosomes in the GnomAD database, including 677,771 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64902 hom., cov: 30)
  • Exomes 𝑓: 0.92 (612869 hom.)
• Consequence: EIF2AK4 NM_001013703.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001672
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.269
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 15-40030351-G-T is Benign according to our data. Variant chr15-40030351-G-T is described in ClinVar as Benign. ClinVar VariationId is 381185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.935 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.4562-8G>T		splice_region intron	N/A	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.4562-8G>T		splice_region intron	N/A	ENSP00000263791.5	Q9P2K8-1
	EIF2AK4	ENST00000558629.5	TSL:1	n.3479-8G>T		splice_region intron	N/A
	EIF2AK4	ENST00000917949.1		c.4604-8G>T		splice_region intron	N/A	ENSP00000588008.1

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140380 AN: 152084 Hom.: 64865 Cov.: 30

Gnomad AFR AF: 0.943

Gnomad AMI AF: 0.949

Gnomad AMR AF: 0.947

Gnomad ASJ AF: 0.900

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.907

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.922

Gnomad OTH AF: 0.930

GnomAD2 exomes AF: 0.914 AC: 226881 AN: 248362 AF XY: 0.912

Gnomad AFR exome AF: 0.941

Gnomad AMR exome AF: 0.966

Gnomad ASJ exome AF: 0.900

Gnomad EAS exome AF: 0.768

Gnomad FIN exome AF: 0.905

Gnomad NFE exome AF: 0.921

Gnomad OTH exome AF: 0.917

GnomAD4 exome AF: 0.915 AC: 1337545 AN: 1461074 Hom.: 612869 Cov.: 38 AF XY: 0.915 AC XY: 664911 AN XY: 726834

African (AFR) AF: 0.941 AC: 31507 AN: 33468

American (AMR) AF: 0.963 AC: 43027 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 23402 AN: 26090

East Asian (EAS) AF: 0.772 AC: 30651 AN: 39696

South Asian (SAS) AF: 0.904 AC: 77876 AN: 86100

European-Finnish (FIN) AF: 0.905 AC: 48305 AN: 53358

Middle Eastern (MID) AF: 0.925 AC: 5336 AN: 5768

European-Non Finnish (NFE) AF: 0.920 AC: 1022825 AN: 1111582

Other (OTH) AF: 0.905 AC: 54616 AN: 60352

GnomAD4 genome AF: 0.923 AC: 140473 AN: 152202 Hom.: 64902 Cov.: 30 AF XY: 0.920 AC XY: 68479 AN XY: 74400

African (AFR) AF: 0.942 AC: 39112 AN: 41516

American (AMR) AF: 0.947 AC: 14489 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 3121 AN: 3466

East Asian (EAS) AF: 0.779 AC: 4031 AN: 5176

South Asian (SAS) AF: 0.907 AC: 4379 AN: 4826

European-Finnish (FIN) AF: 0.899 AC: 9519 AN: 10592

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.922 AC: 62720 AN: 68014

Other (OTH) AF: 0.931 AC: 1969 AN: 2116

Alfa AF: 0.921 Hom.: 221768

Bravo AF: 0.927

EpiCase AF: 0.919

EpiControl AF: 0.920

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.7
DANN	Benign	0.89
PhyloP100		0.27
PromoterAI		0.0041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs2250402; hg19: chr15-40322552; COSMIC: COSV55472359; COSMIC: COSV55472359;