rs6758592

Variant names:

• chr2-46331402-T-C
• rs6758592
• NM_001430.5:c.27-15471T>C

Variant summary

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

The NM_001430.5(EPAS1):​c.27-15471T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 152,120 control chromosomes in the GnomAD database, including 14,609 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 0.42 (14609 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.580
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.27-15471T>C		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.65+5526T>C		intron_variant	Intron 1 of 15		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-15471T>C		intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.27-15471T>C		intron_variant	Intron 2 of 6	3		ENSP00000406137.1
EPAS1	ENST00000460015.1	n.433-15471T>C		intron_variant	Intron 1 of 1	4
EPAS1	ENST00000467888.5	n.175-15471T>C		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64364 AN: 152002 Hom.: 14591 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.417

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

GnomAD4 genome AF: 0.423 AC: 64419 AN: 152120 Hom.: 14609 Cov.: 33 AF XY: 0.430 AC XY: 32002 AN XY: 74340

African (AFR) AF: 0.264 AC: 10958 AN: 41520

American (AMR) AF: 0.579 AC: 8854 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1430 AN: 3468

East Asian (EAS) AF: 0.672 AC: 3474 AN: 5172

South Asian (SAS) AF: 0.444 AC: 2140 AN: 4820

European-Finnish (FIN) AF: 0.505 AC: 5332 AN: 10560

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30865 AN: 67992

Other (OTH) AF: 0.422 AC: 887 AN: 2104

Alfa AF: 0.446 Hom.: 52139

Bravo AF: 0.424

Asia WGS AF: 0.558 AC: 1938 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.1
DANN	Benign	0.78
PhyloP100		-0.58
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: rs6758592; hg19: chr2-46558541;