2-46338383-T-C

Position:

• chr2-46338383-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):​c.27-8490T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 152,142 control chromosomes in the GnomAD database, including 35,013 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 0.66 (35013 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.513

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.27-8490T>C		intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.66-8490T>C		intron_variant			XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-8490T>C		intron_variant		1	NM_001430.5	ENSP00000263734.3

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99624 AN: 152024 Hom.: 34953 Cov.: 32

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.928

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.614

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

GnomAD4 genome AF: 0.656 AC: 99740 AN: 152142 Hom.: 35013 Cov.: 32 AF XY: 0.659 AC XY: 49006 AN XY: 74378

Gnomad4 AFR AF: 0.893

Gnomad4 AMR AF: 0.717

Gnomad4 ASJ AF: 0.546

Gnomad4 EAS AF: 0.928

Gnomad4 SAS AF: 0.648

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.503

Gnomad4 OTH AF: 0.619

Alfa AF: 0.539 Hom.: 30875

Bravo AF: 0.683

Asia WGS AF: 0.802 AC: 2785 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.68

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

LitVar

Other links and lift over

dbSNP: rs4953352; hg19: chr2-46565522;