2-46356096-C-A

Position:

• chr2-46356096-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000263734.5(EPAS1):​c.218-55C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.552 in 1,503,122 control chromosomes in the GnomAD database, including 246,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31652 hom., cov: 30)
  • Exomes 𝑓: 0.54 (214370 hom.)
• Consequence: EPAS1 ENST00000263734.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.575

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-46356096-C-A is Benign according to our data. Variant chr2-46356096-C-A is described in ClinVar as [Benign]. Clinvar id is 1262985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-55C>A		intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-55C>A		intron_variant			XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.218-55C>A		intron_variant		1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.218-55C>A		intron_variant		3		ENSP00000406137.1
EPAS1	ENST00000475822.1	n.409-55C>A		intron_variant		4
EPAS1	ENST00000463191.1	n.-19C>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.633 AC: 95663 AN: 151218 Hom.: 31598 Cov.: 30

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.605

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.642

GnomAD4 exome AF: 0.543 AC: 733495 AN: 1351786 Hom.: 214370 Cov.: 22 AF XY: 0.543 AC XY: 367743 AN XY: 677686

Gnomad4 AFR exome AF: 0.800

Gnomad4 AMR exome AF: 0.778

Gnomad4 ASJ exome AF: 0.591

Gnomad4 EAS exome AF: 0.895

Gnomad4 SAS exome AF: 0.619

Gnomad4 FIN exome AF: 0.561

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.571

GnomAD4 genome AF: 0.633 AC: 95773 AN: 151336 Hom.: 31652 Cov.: 30 AF XY: 0.638 AC XY: 47061 AN XY: 73814

Gnomad4 AFR AF: 0.787

Gnomad4 AMR AF: 0.716

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.883

Gnomad4 SAS AF: 0.637

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.515

Gnomad4 OTH AF: 0.645

Alfa AF: 0.547 Hom.: 25051

Bravo AF: 0.651

Asia WGS AF: 0.766 AC: 2662 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.083
DANN	Benign	0.62

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: rs6743991; hg19: chr2-46583235;