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

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

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-9_218-8insT		splice_region_variant, intron_variant	Intron 2 of 15	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-9_257-8insT		splice_region_variant, intron_variant	Intron 2 of 15		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.218-9_218-8insT		splice_region_variant, intron_variant	Intron 2 of 15	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.218-9_218-8insT		splice_region_variant, intron_variant	Intron 3 of 6	3		ENSP00000406137.1
EPAS1	ENST00000463191.1	n.28_29insT		non_coding_transcript_exon_variant	Exon 1 of 4	2
EPAS1	ENST00000475822.1	n.409-9_409-8insT		splice_region_variant, intron_variant	Intron 2 of 2	4

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

Gnomad4 AFR exome AF: 0.199 AC: 5965 AN: 29950

Gnomad4 AMR exome AF: 0.296 AC: 12361 AN: 41782

Gnomad4 ASJ exome AF: 0.187 AC: 4230 AN: 22680

Gnomad4 EAS exome AF: 0.0814 AC: 3005 AN: 36928

Gnomad4 SAS exome AF: 0.253 AC: 20415 AN: 80652

Gnomad4 FIN exome AF: 0.162 AC: 7742 AN: 47712

Gnomad4 NFE exome AF: 0.131 AC: 114645 AN: 877260

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.232 AC: 0.231971 AN: 0.231971

Gnomad4 AMR AF: 0.254 AC: 0.254286 AN: 0.254286

Gnomad4 ASJ AF: 0.208 AC: 0.208012 AN: 0.208012

Gnomad4 EAS AF: 0.0942 AC: 0.0941856 AN: 0.0941856

Gnomad4 SAS AF: 0.280 AC: 0.27987 AN: 0.27987

Gnomad4 FIN AF: 0.156 AC: 0.156062 AN: 0.156062

Gnomad4 NFE AF: 0.143 AC: 0.142624 AN: 0.142624

Gnomad4 OTH AF: 0.173 AC: 0.173154 AN: 0.173154

Alfa AF: 0.154 Hom.: 165

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial erythrocytosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

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