2-46329622-G-C

Variant names:

• chr2-46329622-G-C
• rs12620992
• NM_001430.5:c.27-17251G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):​c.27-17251G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 151,920 control chromosomes in the GnomAD database, including 25,044 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (25044 hom., cov: 31)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 0 publications found

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]

EPAS1 Gene-Disease associations (from GenCC):

• erythrocytosis, familial, 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001430.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	NM_001430.5	MANE Select	c.27-17251G>C		intron	N/A	NP_001421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.27-17251G>C		intron	N/A	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.27-17251G>C		intron	N/A	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.27-17257G>C		intron	N/A	ENSP00000531876.1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86028 AN: 151802 Hom.: 25022 Cov.: 31

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.547

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.567 AC: 86095 AN: 151920 Hom.: 25044 Cov.: 31 AF XY: 0.574 AC XY: 42648 AN XY: 74248

African (AFR) AF: 0.593 AC: 24521 AN: 41378

American (AMR) AF: 0.659 AC: 10066 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1738 AN: 3470

East Asian (EAS) AF: 0.972 AC: 5031 AN: 5178

South Asian (SAS) AF: 0.612 AC: 2947 AN: 4814

European-Finnish (FIN) AF: 0.556 AC: 5855 AN: 10534

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.501 AC: 34049 AN: 67958

Other (OTH) AF: 0.551 AC: 1161 AN: 2108

Alfa AF: 0.516 Hom.: 2547

Bravo AF: 0.579

Asia WGS AF: 0.775 AC: 2695 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.4
DANN	Benign	0.28
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs12620992; hg19: chr2-46556761;