2-46306237-T-C

Variant summary

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

The NM_001430.5(EPAS1):c.26+8300T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 151,996 control chromosomes in the GnomAD database, including 21,345 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 0.52 (21345 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.633

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.26+8300T>C		intron_variant		ENST00000263734.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.26+8300T>C		intron_variant		1	NM_001430.5	P1
EPAS1	ENST00000449347.5	c.26+8300T>C		intron_variant		3
EPAS1	ENST00000460015.1	n.432+12139T>C		intron_variant, non_coding_transcript_variant		4
EPAS1	ENST00000467888.5	n.174+8300T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78344 AN: 151878 Hom.: 21339 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.541

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

GnomAD4 genome AF: 0.516 AC: 78383 AN: 151996 Hom.: 21345 Cov.: 32 AF XY: 0.513 AC XY: 38104 AN XY: 74294

Gnomad4 AFR AF: 0.378

Gnomad4 AMR AF: 0.615

Gnomad4 ASJ AF: 0.634

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.540

Gnomad4 NFE AF: 0.595

Gnomad4 OTH AF: 0.536

Alfa AF: 0.563 Hom.: 13823

Bravo AF: 0.509

Asia WGS AF: 0.320 AC: 1117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.8
Dann	Benign	0.50

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: rs11894252; hg19: chr2-46533376;