2-46344171-T-C

Variant names:

• chr2-46344171-T-C
• rs2346175
• NM_001430.5:c.27-2702T>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.27-2702T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 152,168 control chromosomes in the GnomAD database, including 32,501 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 0.64 (32501 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.123
• Publications: 4 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.27-2702T>C		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.66-2702T>C		intron_variant	Intron 1 of 15		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-2702T>C		intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96522 AN: 152050 Hom.: 32436 Cov.: 33

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.936

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.604

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

GnomAD4 genome AF: 0.635 AC: 96644 AN: 152168 Hom.: 32501 Cov.: 33 AF XY: 0.639 AC XY: 47500 AN XY: 74378

African (AFR) AF: 0.831 AC: 34489 AN: 41526

American (AMR) AF: 0.710 AC: 10856 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2024 AN: 3470

East Asian (EAS) AF: 0.936 AC: 4853 AN: 5186

South Asian (SAS) AF: 0.618 AC: 2971 AN: 4810

European-Finnish (FIN) AF: 0.524 AC: 5542 AN: 10584

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.498 AC: 33887 AN: 67978

Other (OTH) AF: 0.608 AC: 1285 AN: 2112

Alfa AF: 0.583 Hom.: 14962

Bravo AF: 0.659

Asia WGS AF: 0.800 AC: 2779 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.6
DANN	Benign	0.53
PhyloP100		-0.12
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: rs2346175; hg19: chr2-46571310;