2-46356133-A-ACC

Position:

• chr2-46356133-A-ACC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001430.5(EPAS1):​c.218-9_218-8dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000903 in 1,140,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000090 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPAS1 NM_001430.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0370

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 2-46356133-A-ACC is Benign according to our data. Variant chr2-46356133-A-ACC is described in ClinVar as [Likely_benign]. Clinvar id is 3056233.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-9_218-8dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-9_257-8dup		splice_polypyrimidine_tract_variant, intron_variant			XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.218-9_218-8dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001430.5	ENSP00000263734	P1
EPAS1	ENST00000449347.5	c.218-9_218-8dup		splice_polypyrimidine_tract_variant, intron_variant		3		ENSP00000406137
EPAS1	ENST00000463191.1	n.28_29dup		non_coding_transcript_exon_variant	1/4	2
EPAS1	ENST00000475822.1	n.409-9_409-8dup		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000444 AC: 35 AN: 78862 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000629

Gnomad ASJ AF: 0.00356

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00171

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00685

Gnomad NFE AF: 0.000488

Gnomad OTH AF: 0.000975

GnomAD4 exome AF: 0.0000903 AC: 103 AN: 1140068 Hom.: 0 Cov.: 23 AF XY: 0.000110 AC XY: 63 AN XY: 574360

Gnomad4 AFR exome AF: 0.0000643

Gnomad4 AMR exome AF: 0.0000241

Gnomad4 ASJ exome AF: 0.000772

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000368

Gnomad4 FIN exome AF: 0.0000891

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.000186

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000443 AC: 35 AN: 78934 Hom.: 0 Cov.: 25 AF XY: 0.000452 AC XY: 17 AN XY: 37606

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000628

Gnomad4 ASJ AF: 0.00356

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00171

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000488

Gnomad4 OTH AF: 0.000971

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

EPAS1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs66811540; hg19: chr2-46583272;