2-46297848-G-GC

Position:

• chr2-46297848-G-GC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001430.5(EPAS1):​c.-58dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,584,112 control chromosomes in the GnomAD database, including 2,434 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (193 hom., cov: 31)
  • Exomes 𝑓: 0.053 (2241 hom.)
• Consequence: EPAS1 NM_001430.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.449

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 -16 ACMG points.

• BP6: Variant 2-46297848-G-GC is Benign according to our data. Variant chr2-46297848-G-GC is described in ClinVar as [Benign]. Clinvar id is 336232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.-58dup		5_prime_UTR_variant	1/16	ENST00000263734.5	NP_001421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.-58dup		5_prime_UTR_variant	1/16	1	NM_001430.5	ENSP00000263734	P1
EPAS1	ENST00000449347.5	c.-58dup		5_prime_UTR_variant	2/7	3		ENSP00000406137
EPAS1	ENST00000467888.5	n.91dup		non_coding_transcript_exon_variant	1/3	5
EPAS1	ENST00000460015.1	n.432+3756dup		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0442 AC: 6718 AN: 152014 Hom.: 193 Cov.: 31

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0549

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0587

Gnomad OTH AF: 0.0393

GnomAD4 exome AF: 0.0527 AC: 75451 AN: 1431980 Hom.: 2241 Cov.: 31 AF XY: 0.0515 AC XY: 36590 AN XY: 710172

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.0263

Gnomad4 ASJ exome AF: 0.0524

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.0502

Gnomad4 NFE exome AF: 0.0598

Gnomad4 OTH exome AF: 0.0451

GnomAD4 genome AF: 0.0442 AC: 6720 AN: 152132 Hom.: 193 Cov.: 31 AF XY: 0.0430 AC XY: 3200 AN XY: 74384

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.0345

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0549

Gnomad4 NFE AF: 0.0587

Gnomad4 OTH AF: 0.0389

Alfa AF: 0.0465 Hom.: 29

Bravo AF: 0.0429

Asia WGS AF: 0.0130 AC: 47 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial erythrocytosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs200720368; hg19: chr2-46524987;