chr2-46307199-A-G

Variant names:

• chr2-46307199-A-G
• rs1867785
• NM_001430.5:c.26+9262A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):​c.26+9262A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 152,046 control chromosomes in the GnomAD database, including 21,320 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (21320 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.560
• Publications: 25 publications found

Genes affected

EPAS1 (HGNC:3374): (endothelial PAS domain protein 1) This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall. The encoded protein contains a basic-helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. Mutations in this gene are associated with erythrocytosis familial type 4. [provided by RefSeq, Nov 2009]

EPAS1 Gene-Disease associations (from GenCC):

• erythrocytosis, familial, 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001430.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	NM_001430.5	MANE Select	c.26+9262A>G		intron	N/A	NP_001421.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.26+9262A>G		intron	N/A	ENSP00000263734.3
	EPAS1	ENST00000449347.5	TSL:3	c.26+9262A>G		intron	N/A	ENSP00000406137.1
	EPAS1	ENST00000460015.1	TSL:4	n.432+13101A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78221 AN: 151928 Hom.: 21314 Cov.: 32

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.539

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.515 AC: 78259 AN: 152046 Hom.: 21320 Cov.: 32 AF XY: 0.512 AC XY: 38071 AN XY: 74324

African (AFR) AF: 0.372 AC: 15444 AN: 41464

American (AMR) AF: 0.615 AC: 9407 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 2190 AN: 3472

East Asian (EAS) AF: 0.167 AC: 861 AN: 5168

South Asian (SAS) AF: 0.476 AC: 2295 AN: 4824

European-Finnish (FIN) AF: 0.542 AC: 5720 AN: 10554

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40478 AN: 67950

Other (OTH) AF: 0.533 AC: 1126 AN: 2112

Alfa AF: 0.566 Hom.: 92945

Bravo AF: 0.508

Asia WGS AF: 0.319 AC: 1112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Benign	0.63
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1867785; hg19: chr2-46534338;