2-46356142-C-CAT

Variant names:

• chr2-46356142-C-CAT
• rs35508970
• NM_001430.5:c.218-9_218-8insAT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001430.5(EPAS1):​c.218-9_218-8insAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000812 in 1,231,194 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: EPAS1 NM_001430.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.628
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.218-9_218-8insAT		splice_region intron	N/A	NP_001421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.218-9_218-8insAT		splice_region intron	N/A	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.218-9_218-8insAT		splice_region intron	N/A	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.212-9_212-8insAT		splice_region intron	N/A	ENSP00000531876.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 8.12e-7 AC: 1 AN: 1231194 Hom.: 0 Cov.: 34 AF XY: 0.00000162 AC XY: 1 AN XY: 618466

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32184

American (AMR) AF: 0.00 AC: 0 AN: 43464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23642

East Asian (EAS) AF: 0.00 AC: 0 AN: 39078

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 904480

Other (OTH) AF: 0.00 AC: 0 AN: 52108

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35508970; hg19: chr2-46583281;