2-46356142-C-CT

Variant names:

• chr2-46356142-C-CT
• rs35508970
• NM_001430.5:c.218-9_218-8insT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001430.5(EPAS1):​c.218-9_218-8insT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,191,614 control chromosomes in the GnomAD database, including 7,274 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2444 hom., cov: 23)
  • Exomes 𝑓: 0.15 (7274 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPAS1 NM_001430.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.628
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 2-46356142-C-CT is Benign according to our data. Variant chr2-46356142-C-CT is described in ClinVar as Benign. ClinVar VariationId is 336245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

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_218-8insT		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_218-8insT		splice_region intron	N/A	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.218-9_218-8insT		splice_region intron	N/A	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.212-9_212-8insT		splice_region intron	N/A	ENSP00000531876.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 26281 AN: 143690 Hom.: 2435 Cov.: 23

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.0940

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.148 AC: 176441 AN: 1191614 Hom.: 7274 Cov.: 34 AF XY: 0.151 AC XY: 90343 AN XY: 598802

African (AFR) AF: 0.199 AC: 5965 AN: 29950

American (AMR) AF: 0.296 AC: 12361 AN: 41782

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4230 AN: 22680

East Asian (EAS) AF: 0.0814 AC: 3005 AN: 36928

South Asian (SAS) AF: 0.253 AC: 20415 AN: 80652

European-Finnish (FIN) AF: 0.162 AC: 7742 AN: 47712

Middle Eastern (MID) AF: 0.164 AC: 751 AN: 4582

European-Non Finnish (NFE) AF: 0.131 AC: 114645 AN: 877260

Other (OTH) AF: 0.146 AC: 7327 AN: 50068

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.183 AC: 26319 AN: 143808 Hom.: 2444 Cov.: 23 AF XY: 0.185 AC XY: 12877 AN XY: 69572

African (AFR) AF: 0.232 AC: 9103 AN: 39242

American (AMR) AF: 0.254 AC: 3619 AN: 14232

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 701 AN: 3370

East Asian (EAS) AF: 0.0942 AC: 473 AN: 5022

South Asian (SAS) AF: 0.280 AC: 1204 AN: 4302

European-Finnish (FIN) AF: 0.156 AC: 1403 AN: 8990

Middle Eastern (MID) AF: 0.138 AC: 39 AN: 282

European-Non Finnish (NFE) AF: 0.143 AC: 9339 AN: 65480

Other (OTH) AF: 0.173 AC: 347 AN: 2004

Alfa AF: 0.154 Hom.: 165

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial erythrocytosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
Mutation Taster		=20/80	disease causing

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: rs35508970; hg19: chr2-46583281; COSMIC: COSV105052099;