chr2-46368224-G-A

Position:

• chr2-46368224-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):​c.780-1603G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.091 in 152,206 control chromosomes in the GnomAD database, including 789 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 0.091 (789 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.661

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.780-1603G>A		intron_variant		ENST00000263734.5
EPAS1	XM_011532698.3	c.819-1603G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.780-1603G>A		intron_variant		1	NM_001430.5	P1

Frequencies

GnomAD3 genomes AF: 0.0910 AC: 13845 AN: 152088 Hom.: 787 Cov.: 33

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0969

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

GnomAD4 genome AF: 0.0910 AC: 13853 AN: 152206 Hom.: 789 Cov.: 33 AF XY: 0.0918 AC XY: 6831 AN XY: 74412

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0919

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.100

Alfa AF: 0.113 Hom.: 1298

Bravo AF: 0.0854

Asia WGS AF: 0.125 AC: 433 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	0.56
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs4145836; hg19: chr2-46595363;