2-46296516-G-C

Variant names:

• chr2-46296516-G-C
• rs56721780
• ENST00000460015.1:n.432+2418G>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+2418G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 152,378 control chromosomes in the GnomAD database, including 2,436 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 0.14 (2435 hom., cov: 32)
  • Exomes 𝑓: 0.070 (1 hom.)
• Consequence: EPAS1 ENST00000460015.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 8 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.312 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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000460015.1	TSL:4	n.432+2418G>C		intron	N/A
	ENSG00000304136	ENST00000799986.1		n.118+618C>G		intron	N/A
	ENSG00000304136	ENST00000799987.1		n.42+618C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21037 AN: 152132 Hom.: 2413 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0840

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0733

Gnomad OTH AF: 0.115

GnomAD4 exome AF: 0.0703 AC: 9 AN: 128 Hom.: 1 AF XY: 0.0400 AC XY: 4 AN XY: 100

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0761 AC: 7 AN: 92

Other (OTH) AF: 0.100 AC: 1 AN: 10

GnomAD4 genome AF: 0.139 AC: 21104 AN: 152250 Hom.: 2435 Cov.: 32 AF XY: 0.136 AC XY: 10088 AN XY: 74450

African (AFR) AF: 0.316 AC: 13127 AN: 41508

American (AMR) AF: 0.0838 AC: 1283 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3470

East Asian (EAS) AF: 0.0156 AC: 81 AN: 5186

South Asian (SAS) AF: 0.0765 AC: 369 AN: 4824

European-Finnish (FIN) AF: 0.0574 AC: 609 AN: 10618

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0734 AC: 4989 AN: 68016

Other (OTH) AF: 0.114 AC: 240 AN: 2110

Alfa AF: 0.105 Hom.: 183

Bravo AF: 0.149

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.38
DANN	Benign	0.66
PhyloP100		-1.5
PromoterAI		-0.0050	Neutral

Splicing

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

Other links and lift over

dbSNP: rs56721780; hg19: chr2-46523655;