chr2-46343569-C-G

Variant names:

• chr2-46343569-C-G
• rs1868084
• NM_001430.5:c.27-3304C>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.27-3304C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,212 control chromosomes in the GnomAD database, including 1,891 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 (1891 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680
• 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.219 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	NM_001430.5	MANE Select	c.27-3304C>G		intron	N/A	NP_001421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.27-3304C>G		intron	N/A	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.27-3304C>G		intron	N/A	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.27-3310C>G		intron	N/A	ENSP00000531876.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21685 AN: 152092 Hom.: 1884 Cov.: 33

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.143 AC: 21700 AN: 152212 Hom.: 1891 Cov.: 33 AF XY: 0.145 AC XY: 10797 AN XY: 74422

African (AFR) AF: 0.0364 AC: 1511 AN: 41546

American (AMR) AF: 0.225 AC: 3441 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 511 AN: 3472

East Asian (EAS) AF: 0.184 AC: 952 AN: 5176

South Asian (SAS) AF: 0.111 AC: 537 AN: 4832

European-Finnish (FIN) AF: 0.207 AC: 2188 AN: 10574

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12130 AN: 68008

Other (OTH) AF: 0.148 AC: 311 AN: 2108

Alfa AF: 0.157 Hom.: 249

Bravo AF: 0.140

Asia WGS AF: 0.177 AC: 616 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.75
PhyloP100		0.068
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: rs1868084; hg19: chr2-46570708;