2-46340088-A-G

Variant summary

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

The NM_001430.5(EPAS1):c.27-6785A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 152,034 control chromosomes in the GnomAD database, including 29,318 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 0.60 (29318 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660

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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.27-6785A>G		intron_variant		ENST00000263734.5
EPAS1	XM_011532698.3	c.66-6785A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-6785A>G		intron_variant		1	NM_001430.5	P1

Frequencies

GnomAD3 genomes AF: 0.599 AC: 91065 AN: 151916 Hom.: 29260 Cov.: 32

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.576

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

GnomAD4 genome AF: 0.600 AC: 91179 AN: 152034 Hom.: 29318 Cov.: 32 AF XY: 0.602 AC XY: 44734 AN XY: 74296

Gnomad4 AFR AF: 0.801

Gnomad4 AMR AF: 0.668

Gnomad4 ASJ AF: 0.549

Gnomad4 EAS AF: 0.923

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.453

Gnomad4 NFE AF: 0.463

Gnomad4 OTH AF: 0.581

Alfa AF: 0.455 Hom.: 2934

Bravo AF: 0.628

Asia WGS AF: 0.776 AC: 2697 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	3.1
Dann	Benign	0.71

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: rs4035887; hg19: chr2-46567227;