2-46343569-C-G

Position:

• chr2-46343569-C-G

Variant summary

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

The NM_001430.5(EPAS1):​c.27-3304C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,212 control chromosomes in the GnomAD database, including 1,891 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 0.14 (1891 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.27-3304C>G		intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.66-3304C>G		intron_variant			XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-3304C>G		intron_variant		1	NM_001430.5	ENSP00000263734.3

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21685 AN: 152092 Hom.: 1884 Cov.: 33

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.143 AC: 21700 AN: 152212 Hom.: 1891 Cov.: 33 AF XY: 0.145 AC XY: 10797 AN XY: 74422

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.148

Alfa AF: 0.157 Hom.: 249

Bravo AF: 0.140

Asia WGS AF: 0.177 AC: 616 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.75

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: rs1868084; hg19: chr2-46570708;