NM_001430.5:c.26+2464G>C

Variant names:

• chr2-46300401-G-C
• rs1867782
• NM_001430.5:c.26+2464G>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.26+2464G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.934 in 152,310 control chromosomes in the GnomAD database, including 66,523 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 0.93 (66523 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 4 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 = 0.945 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+2464G>C		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+2464G>C		intron	N/A	ENSP00000263734.3
	EPAS1	ENST00000449347.5	TSL:3	c.26+2464G>C		intron	N/A	ENSP00000406137.1
	EPAS1	ENST00000460015.1	TSL:4	n.432+6303G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.934 AC: 142183 AN: 152192 Hom.: 66463 Cov.: 33

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.948

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.923

Gnomad FIN AF: 0.936

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.922

Gnomad OTH AF: 0.936

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

GnomAD4 genome AF: 0.934 AC: 142301 AN: 152310 Hom.: 66523 Cov.: 33 AF XY: 0.936 AC XY: 69709 AN XY: 74462

African (AFR) AF: 0.953 AC: 39611 AN: 41562

American (AMR) AF: 0.949 AC: 14516 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3191 AN: 3470

East Asian (EAS) AF: 0.958 AC: 4960 AN: 5176

South Asian (SAS) AF: 0.923 AC: 4459 AN: 4830

European-Finnish (FIN) AF: 0.936 AC: 9940 AN: 10618

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.922 AC: 62706 AN: 68030

Other (OTH) AF: 0.937 AC: 1981 AN: 2114

Alfa AF: 0.932 Hom.: 8293

Bravo AF: 0.935

Asia WGS AF: 0.940 AC: 3268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.40
PhyloP100		-1.0
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: rs1867782; hg19: chr2-46527540;