chr2-46350505-G-A

Position:

• chr2-46350505-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.217+3442G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,184 control chromosomes in the GnomAD database, including 2,947 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 0.19 (2947 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.801

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=-0.74).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.217+3442G>A		intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.256+3442G>A		intron_variant			XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.217+3442G>A		intron_variant		1	NM_001430.5	ENSP00000263734	P1
EPAS1	ENST00000449347.5	c.217+3442G>A		intron_variant		3		ENSP00000406137
EPAS1	ENST00000475822.1	n.408+3442G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28603 AN: 152066 Hom.: 2946 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.0990

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.188 AC: 28614 AN: 152184 Hom.: 2947 Cov.: 33 AF XY: 0.189 AC XY: 14063 AN XY: 74416

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.0992

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.202

Alfa AF: 0.197 Hom.: 1225

Bravo AF: 0.195

Asia WGS AF: 0.160 AC: 558 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.6
DANN	Benign	0.87

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: rs10187368; hg19: chr2-46577644;