Genetic Variant EPAS1:c.26+16100T>C (chr2-46314037-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001430.5(EPAS1):c.26+16100T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 152,118 control chromosomes in the GnomAD database, including 20,520 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 0.50 ( 20520 hom., cov: 32)

Consequence

EPAS1
NM_001430.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.43

Publications

17 publications found

Variant links:

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

EPAS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5 link	c.26+16100T>C		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2	Q99814B3KW07
EPAS1	XM_011532698.3 link	c.-11775T>C		5_prime_UTR_variant	Exon 1 of 16		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPAS1	ENST00000263734.5 link	c.26+16100T>C	intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3	Q99814
EPAS1	ENST00000449347.5 link	c.26+16100T>C	intron_variant	Intron 2 of 6	3		ENSP00000406137.1	C9J9N2
EPAS1	ENST00000460015.1 link	n.432+19939T>C	intron_variant	Intron 1 of 1	4
EPAS1	ENST00000467888.5 link	n.174+16100T>C	intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.501

AC:

76101

AN:

152000

Hom.:

20522

Cov.:

show subpopulations

Gnomad AFR

AF:

0.328

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.611

Gnomad ASJ

AF:

0.628

Gnomad EAS

AF:

0.154

Gnomad SAS

AF:

0.473

Gnomad FIN

AF:

0.539

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.593

Gnomad OTH

AF:

0.536

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

GnomAD4 genome

AF:

0.500

AC:

76118

AN:

152118

Hom.:

20520

Cov.:

AF XY:

0.498

AC XY:

37070

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.328

AC:

13592

AN:

41476

American (AMR)

AF:

0.611

AC:

9342

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.628

AC:

2180

AN:

3470

East Asian (EAS)

AF:

0.154

AC:

799

AN:

5184

South Asian (SAS)

AF:

0.473

AC:

2281

AN:

4826

European-Finnish (FIN)

AF:

0.539

AC:

5707

AN:

10594

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.593

AC:

40321

AN:

67964

Other (OTH)

AF:

0.530

AC:

1119

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1843

3685

5528

7370

9213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

664

1328

1992

2656

3320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.553

Hom.:

9976

Bravo

AF:

0.492

Asia WGS

AF:

0.300

AC:

1048

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over