2-46306237-T-C

Variant names:

• chr2-46306237-T-C
• rs11894252
• NM_001430.5:c.26+8300T>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+8300T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 151,996 control chromosomes in the GnomAD database, including 21,345 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 0.52 (21345 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.633
• Publications: 26 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.605 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.26+8300T>C		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.26+8300T>C		intron	N/A	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.26+8300T>C		intron	N/A	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.26+8300T>C		intron	N/A	ENSP00000531876.1

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78344 AN: 151878 Hom.: 21339 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.541

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

GnomAD4 genome AF: 0.516 AC: 78383 AN: 151996 Hom.: 21345 Cov.: 32 AF XY: 0.513 AC XY: 38104 AN XY: 74294

African (AFR) AF: 0.378 AC: 15646 AN: 41432

American (AMR) AF: 0.615 AC: 9399 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2200 AN: 3468

East Asian (EAS) AF: 0.169 AC: 874 AN: 5184

South Asian (SAS) AF: 0.475 AC: 2295 AN: 4828

European-Finnish (FIN) AF: 0.540 AC: 5692 AN: 10532

Middle Eastern (MID) AF: 0.637 AC: 186 AN: 292

European-Non Finnish (NFE) AF: 0.595 AC: 40414 AN: 67966

Other (OTH) AF: 0.536 AC: 1128 AN: 2106

Alfa AF: 0.569 Hom.: 20246

Bravo AF: 0.509

Asia WGS AF: 0.320 AC: 1117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.50
PhyloP100		-0.63
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: rs11894252; hg19: chr2-46533376;