2-46356142-C-T

Position:

• chr2-46356142-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001430.5(EPAS1):​c.218-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16488 hom., cov: 24)
  • Exomes 𝑓: 0.46 (120080 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPAS1 NM_001430.5 intron
• Scores: Splicing: ADA: 0.00003178
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.83

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=-0.72).
• BP6: Variant 2-46356142-C-T is Benign according to our data. Variant chr2-46356142-C-T is described in ClinVar as [Benign]. Clinvar id is 336246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-46356142-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-9C>T		intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-9C>T		intron_variant			XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.218-9C>T		intron_variant		1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.218-9C>T		intron_variant		3		ENSP00000406137.1
EPAS1	ENST00000463191.1	n.28C>T		non_coding_transcript_exon_variant	1/4	2
EPAS1	ENST00000475822.1	n.409-9C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 67994 AN: 144920 Hom.: 16454 Cov.: 24 FAILED QC

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.483

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.462 AC: 563545 AN: 1219682 Hom.: 120080 Cov.: 32 AF XY: 0.454 AC XY: 278018 AN XY: 612278

Gnomad4 AFR exome AF: 0.630

Gnomad4 AMR exome AF: 0.470

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.799

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.427

Gnomad4 NFE exome AF: 0.452

Gnomad4 OTH exome AF: 0.479

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.469 AC: 68070 AN: 145036 Hom.: 16488 Cov.: 24 AF XY: 0.473 AC XY: 33278 AN XY: 70282

Gnomad4 AFR AF: 0.593

Gnomad4 AMR AF: 0.469

Gnomad4 ASJ AF: 0.395

Gnomad4 EAS AF: 0.794

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.434

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.489

Alfa AF: 0.355 Hom.: 1160

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Erythrocytosis, familial, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0020
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: rs75984373; hg19: chr2-46583281;