rs4952818

Variant names:

• chr2-46309917-C-T
• rs4952818
• NM_001430.5:c.26+11980C>T

Variant summary

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

The NM_001430.5(EPAS1):​c.26+11980C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,124 control chromosomes in the GnomAD database, including 14,389 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 0.39 (14389 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.503
• Publications: 12 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.26+11980C>T		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.26+11980C>T		intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.26+11980C>T		intron_variant	Intron 2 of 6	3		ENSP00000406137.1
EPAS1	ENST00000460015.1	n.432+15819C>T		intron_variant	Intron 1 of 1	4
EPAS1	ENST00000467888.5	n.174+11980C>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59215 AN: 152006 Hom.: 14390 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.433

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

GnomAD4 genome AF: 0.389 AC: 59224 AN: 152124 Hom.: 14389 Cov.: 32 AF XY: 0.390 AC XY: 28970 AN XY: 74358

African (AFR) AF: 0.109 AC: 4511 AN: 41532

American (AMR) AF: 0.536 AC: 8193 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1909 AN: 3472

East Asian (EAS) AF: 0.144 AC: 745 AN: 5174

South Asian (SAS) AF: 0.435 AC: 2095 AN: 4818

European-Finnish (FIN) AF: 0.471 AC: 4970 AN: 10552

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35318 AN: 67968

Other (OTH) AF: 0.428 AC: 904 AN: 2110

Alfa AF: 0.495 Hom.: 17809

Bravo AF: 0.375

Asia WGS AF: 0.266 AC: 927 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.9
DANN	Benign	0.61
PhyloP100		0.50
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: rs4952818; hg19: chr2-46537056;