rs6756667

Variant names:

• chr2-46352270-A-G
• rs6756667
• NM_001430.5:c.218-3881A>G

Variant summary

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

The NM_001430.5(EPAS1):​c.218-3881A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 152,032 control chromosomes in the GnomAD database, including 30,341 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 0.62 (30341 hom., cov: 31)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-3881A>G		intron_variant	Intron 2 of 15	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-3881A>G		intron_variant	Intron 2 of 15		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.218-3881A>G		intron_variant	Intron 2 of 15	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.218-3881A>G		intron_variant	Intron 3 of 6	3		ENSP00000406137.1
EPAS1	ENST00000475822.1	n.409-3881A>G		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94260 AN: 151914 Hom.: 30282 Cov.: 31

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.887

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.615

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

GnomAD4 genome AF: 0.621 AC: 94378 AN: 152032 Hom.: 30341 Cov.: 31 AF XY: 0.626 AC XY: 46521 AN XY: 74308

Gnomad4 AFR AF: 0.750

Gnomad4 AMR AF: 0.708

Gnomad4 ASJ AF: 0.599

Gnomad4 EAS AF: 0.887

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.552

Gnomad4 NFE AF: 0.513

Gnomad4 OTH AF: 0.618

Alfa AF: 0.551 Hom.: 19010

Bravo AF: 0.638

Asia WGS AF: 0.761 AC: 2645 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.82
DANN	Benign	0.42

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: rs6756667; hg19: chr2-46579409;