2-46356142-C-CCT

Position:

• chr2-46356142-C-CCT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001430.5(EPAS1):​c.218-8_218-7dup 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 0.00139 in 1,374,212 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 23)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: EPAS1 NM_001430.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.628

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 -6 ACMG points.

• BP6: Variant 2-46356142-C-CCT is Benign according to our data. Variant chr2-46356142-C-CCT is described in ClinVar as [Likely_benign]. Clinvar id is 336244.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 483 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-8_218-7dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-8_257-7dup		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.218-8_218-7dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001430.5	ENSP00000263734	P1
EPAS1	ENST00000449347.5	c.218-8_218-7dup		splice_polypyrimidine_tract_variant, intron_variant		3		ENSP00000406137
EPAS1	ENST00000463191.1	n.29_30dup		non_coding_transcript_exon_variant	1/4	2
EPAS1	ENST00000475822.1	n.409-8_409-7dup		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 482 AN: 144834 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000691

Gnomad FIN AF: 0.000219

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000396

Gnomad OTH AF: 0.00251

GnomAD4 exome AF: 0.00117 AC: 1433 AN: 1229260 Hom.: 8 Cov.: 34 AF XY: 0.00106 AC XY: 652 AN XY: 617610

Gnomad4 AFR exome AF: 0.00510

Gnomad4 AMR exome AF: 0.000994

Gnomad4 ASJ exome AF: 0.000338

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.000790

Gnomad4 FIN exome AF: 0.0000612

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00333 AC: 483 AN: 144952 Hom.: 3 Cov.: 23 AF XY: 0.00329 AC XY: 231 AN XY: 70260

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.00145

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000395

Gnomad4 SAS AF: 0.000692

Gnomad4 FIN AF: 0.000219

Gnomad4 NFE AF: 0.000396

Gnomad4 OTH AF: 0.00249

Alfa AF: 0.00375 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

EPAS1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

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

Familial erythrocytosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs1553394876; hg19: chr2-46583281;