rs59862329

Variant names:

• chr2-46296324-T-C
• rs59862329
• ENST00000460015.1:n.432+2226T>C

Variant summary

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

The ENST00000460015.1(EPAS1):​n.432+2226T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 152,138 control chromosomes in the GnomAD database, including 3,424 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 0.12 (3424 hom., cov: 32)
• Consequence: EPAS1 ENST00000460015.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.505
• Publications: 2 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

ENSG00000304136 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000460015.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000460015.1	TSL:4	n.432+2226T>C		intron	N/A
	ENSG00000304136	ENST00000799986.1		n.118+810A>G		intron	N/A
	ENSG00000304136	ENST00000799987.1		n.42+810A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17901 AN: 152020 Hom.: 3419 Cov.: 32

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00869

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.0828

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

GnomAD4 genome AF: 0.118 AC: 17928 AN: 152138 Hom.: 3424 Cov.: 32 AF XY: 0.114 AC XY: 8448 AN XY: 74360

African (AFR) AF: 0.401 AC: 16640 AN: 41448

American (AMR) AF: 0.0464 AC: 709 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00852 AC: 44 AN: 5166

South Asian (SAS) AF: 0.0526 AC: 254 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 68006

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.130 Hom.: 2034

Bravo AF: 0.134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.9
DANN	Benign	0.62
PhyloP100		0.51
PromoterAI		0.051	Neutral

Splicing

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

Other links and lift over

dbSNP: rs59862329; hg19: chr2-46523463;