chr2-46377925-T-C

Variant names:

• chr2-46377925-T-C
• rs947956425
• NM_001430.5:c.1281T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001430.5(EPAS1):​c.1281T>C​(p.Tyr427Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,554,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: EPAS1 NM_001430.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.16
• Publications: 0 publications found

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]

LINC01820 (HGNC:52625): (long intergenic non-protein coding RNA 1820)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-46377925-T-C is Benign according to our data. Variant chr2-46377925-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435064.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 32 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001430.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	NM_001430.5	MANE Select	c.1281T>C	p.Tyr427Tyr	synonymous	Exon 10 of 16	NP_001421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.1281T>C	p.Tyr427Tyr	synonymous	Exon 10 of 16	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.1281T>C	p.Tyr427Tyr	synonymous	Exon 10 of 16	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.1275T>C	p.Tyr425Tyr	synonymous	Exon 10 of 16	ENSP00000531876.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000377 AC: 6 AN: 159088 AF XY: 0.0000476

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000973

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 32 AN: 1402136 Hom.: 0 Cov.: 32 AF XY: 0.0000202 AC XY: 14 AN XY: 691820

African (AFR) AF: 0.00 AC: 0 AN: 31730

American (AMR) AF: 0.00 AC: 0 AN: 36090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 35968

South Asian (SAS) AF: 0.00 AC: 0 AN: 79426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000278 AC: 30 AN: 1080470

Other (OTH) AF: 0.0000344 AC: 2 AN: 58106

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Erythrocytosis, familial, 4 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.40
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs947956425; hg19: chr2-46605064;