rs6753127

Positions:

• chr2-46370157-T-C
• chr2-46370157-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001430.5(EPAS1):​c.886+224T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 152,286 control chromosomes in the GnomAD database, including 66,572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.93 (66572 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.27

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-46370157-T-C is Benign according to our data. Variant chr2-46370157-T-C is described in ClinVar as [Benign]. Clinvar id is 1292846.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.886+224T>C		intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.925+224T>C		intron_variant			XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.886+224T>C		intron_variant		1	NM_001430.5	ENSP00000263734	P1

Frequencies

GnomAD3 genomes AF: 0.935 AC: 142211 AN: 152168 Hom.: 66518 Cov.: 32

Gnomad AFR AF: 0.984

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.935

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.916

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.885

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.935

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

GnomAD4 genome AF: 0.935 AC: 142321 AN: 152286 Hom.: 66572 Cov.: 32 AF XY: 0.933 AC XY: 69472 AN XY: 74458

Gnomad4 AFR AF: 0.984

Gnomad4 AMR AF: 0.934

Gnomad4 ASJ AF: 0.931

Gnomad4 EAS AF: 0.916

Gnomad4 SAS AF: 0.895

Gnomad4 FIN AF: 0.885

Gnomad4 NFE AF: 0.916

Gnomad4 OTH AF: 0.933

Alfa AF: 0.919 Hom.: 36895

Bravo AF: 0.942

Asia WGS AF: 0.895 AC: 3115 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6753127; hg19: chr2-46597296;