2-46356139-C-A

Position:

• chr2-46356139-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001430.5(EPAS1):​c.218-12C>A 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 0.00721 in 1,353,870 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 26)
  • Exomes 𝑓: 0.0074 (81 hom.)
• Consequence: EPAS1 NM_001430.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003264
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0460

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-46356139-C-A is Benign according to our data. Variant chr2-46356139-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 336237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 717 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-12C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-12C>A		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.218-12C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001430.5	ENSP00000263734	P1
EPAS1	ENST00000449347.5	c.218-12C>A		splice_polypyrimidine_tract_variant, intron_variant		3		ENSP00000406137
EPAS1	ENST00000463191.1	n.25C>A		non_coding_transcript_exon_variant	1/4	2
EPAS1	ENST00000475822.1	n.409-12C>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 717 AN: 136062 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00354

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00946

Gnomad OTH AF: 0.00484

GnomAD4 exome AF: 0.00742 AC: 9039 AN: 1217708 Hom.: 81 Cov.: 30 AF XY: 0.00718 AC XY: 4397 AN XY: 612346

Gnomad4 AFR exome AF: 0.00107

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.0000843

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.00549

Gnomad4 NFE exome AF: 0.00937

Gnomad4 OTH exome AF: 0.00509

GnomAD4 genome AF: 0.00527 AC: 717 AN: 136162 Hom.: 4 Cov.: 26 AF XY: 0.00482 AC XY: 317 AN XY: 65796

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000825

Gnomad4 FIN AF: 0.00354

Gnomad4 NFE AF: 0.00946

Gnomad4 OTH AF: 0.00479

Alfa AF: 0.00360 Hom.: 3

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	EPAS1: BS2 -
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	-0.84
CADD	Benign	0.73
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.042
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: rs202210836; hg19: chr2-46583278;