2-46356140-C-T

Position:

• chr2-46356140-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.218-11C>T variant causes a splice polypyrimidine tract, 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 0.057 (476 hom., cov: 26)
  • Exomes 𝑓: 0.026 (1582 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPAS1 NM_001430.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002739
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.134

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=-0.9).
• BP6: Variant 2-46356140-C-T is Benign according to our data. Variant chr2-46356140-C-T is described in ClinVar as [Benign]. Clinvar id is 336242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-11C>T		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.218-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001430.5	ENSP00000263734	P1
EPAS1	ENST00000449347.5	c.218-11C>T		splice_polypyrimidine_tract_variant, intron_variant		3		ENSP00000406137
EPAS1	ENST00000463191.1	n.26C>T		non_coding_transcript_exon_variant	1/4	2
EPAS1	ENST00000475822.1	n.409-11C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7833 AN: 136704 Hom.: 471 Cov.: 26 FAILED QC

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0513

Gnomad AMR AF: 0.0313

Gnomad ASJ AF: 0.00787

Gnomad EAS AF: 0.00936

Gnomad SAS AF: 0.00908

Gnomad FIN AF: 0.00649

Gnomad MID AF: 0.0203

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0514

GnomAD3 exomes AF: 0.0312 AC: 5428 AN: 173748 Hom.: 926 AF XY: 0.0268 AC XY: 2539 AN XY: 94850

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0201

Gnomad ASJ exome AF: 0.00848

Gnomad EAS exome AF: 0.0123

Gnomad SAS exome AF: 0.00589

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0294

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0265 AC: 32478 AN: 1227202 Hom.: 1582 Cov.: 31 AF XY: 0.0252 AC XY: 15527 AN XY: 616626

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.00748

Gnomad4 EAS exome AF: 0.00453

Gnomad4 SAS exome AF: 0.00519

Gnomad4 FIN exome AF: 0.00723

Gnomad4 NFE exome AF: 0.0265

Gnomad4 OTH exome AF: 0.0300

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0574 AC: 7854 AN: 136810 Hom.: 476 Cov.: 26 AF XY: 0.0542 AC XY: 3589 AN XY: 66192

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.0311

Gnomad4 ASJ AF: 0.00787

Gnomad4 EAS AF: 0.00918

Gnomad4 SAS AF: 0.00824

Gnomad4 FIN AF: 0.00649

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0514

Alfa AF: 0.0264 Hom.: 35

Bravo AF: 0.461

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

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	-0.90
CADD	Benign	0.76
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0
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: rs75591953; hg19: chr2-46583279;