2-46356153-T-G

Position:

• chr2-46356153-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000263734.5(EPAS1):​c.220T>G​(p.Cys74Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000724 in 1,105,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C74R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: EPAS1 ENST00000263734.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18770736).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.220T>G	p.Cys74Gly	missense_variant, splice_region_variant	3/16	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.259T>G	p.Cys87Gly	missense_variant, splice_region_variant	3/16		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.220T>G	p.Cys74Gly	missense_variant, splice_region_variant	3/16	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.220T>G	p.Cys74Gly	missense_variant, splice_region_variant	4/7	3		ENSP00000406137.1
EPAS1	ENST00000463191.1	n.39T>G		non_coding_transcript_exon_variant	1/4	2
EPAS1	ENST00000475822.1	n.411T>G		splice_region_variant, non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000724 AC: 8 AN: 1105704 Hom.: 0 Cov.: 36 AF XY: 0.00000718 AC XY: 4 AN XY: 557090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000996

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2024

The p.C74G variant (also known as c.220T>G), located in coding exon 3 of the EPAS1 gene, results from a T to G substitution at nucleotide position 220. The cysteine at codon 74 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Benign	0.80
DEOGEN2	Benign	0.37	.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.091
Sift	Benign	0.41	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0010	.;B
Vest4		0.76
MutPred		0.40		Gain of disorder (P = 0.0189);Gain of disorder (P = 0.0189);
MVP		0.22
MPC		0.17
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.22
gMVP		0.38

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: rs748761768; hg19: chr2-46583292;