2-46355243-G-A

Position:

• chr2-46355243-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.218-908G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 152,086 control chromosomes in the GnomAD database, including 9,310 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 0.33 (9310 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504

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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.218-908G>A		intron_variant		ENST00000263734.5
EPAS1	XM_011532698.3	c.257-908G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.218-908G>A		intron_variant		1	NM_001430.5	P1
EPAS1	ENST00000449347.5	c.218-908G>A		intron_variant		3
EPAS1	ENST00000475822.1	n.409-908G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50537 AN: 151968 Hom.: 9283 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.330

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

GnomAD4 genome AF: 0.333 AC: 50594 AN: 152086 Hom.: 9310 Cov.: 32 AF XY: 0.338 AC XY: 25145 AN XY: 74350

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.368

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.768

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.303

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.336

Alfa AF: 0.260 Hom.: 2879

Bravo AF: 0.341

Asia WGS AF: 0.534 AC: 1854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.36
DANN	Benign	0.42

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: rs7589621; hg19: chr2-46582382;