chr2-46336253-C-G

Variant names:

• chr2-46336253-C-G
• rs6706003
• NM_001430.5:c.27-10620C>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.27-10620C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 152,082 control chromosomes in the GnomAD database, including 34,326 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 0.64 (34326 hom., cov: 31)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.27-10620C>G		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.65+10377C>G		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.27-10620C>G		intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97857 AN: 151964 Hom.: 34261 Cov.: 31

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.963

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.606

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

GnomAD4 genome AF: 0.644 AC: 97981 AN: 152082 Hom.: 34326 Cov.: 31 AF XY: 0.648 AC XY: 48146 AN XY: 74344

African (AFR) AF: 0.902 AC: 37443 AN: 41506

American (AMR) AF: 0.692 AC: 10568 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1860 AN: 3468

East Asian (EAS) AF: 0.963 AC: 4983 AN: 5176

South Asian (SAS) AF: 0.621 AC: 2988 AN: 4808

European-Finnish (FIN) AF: 0.509 AC: 5377 AN: 10562

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32733 AN: 67966

Other (OTH) AF: 0.610 AC: 1290 AN: 2114

Alfa AF: 0.556 Hom.: 3191

Bravo AF: 0.674

Asia WGS AF: 0.809 AC: 2813 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.040
DANN	Benign	0.24
PhyloP100		-2.3
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: rs6706003; hg19: chr2-46563392;