rs2228321

Positions:

• chr1-21233587-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001397.3(ECE1):​c.1641T>C​(p.Asp547=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0545 in 1,613,554 control chromosomes in the GnomAD database, including 7,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3183 hom., cov: 32)
  • Exomes 𝑓: 0.046 (3819 hom.)
• Consequence: ECE1 NM_001397.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.01

Genes affected

ECE1 (HGNC:3146): (endothelin converting enzyme 1) The protein encoded by this gene is involved in proteolytic processing of endothelin precursors to biologically active peptides. Mutations in this gene are associated with Hirschsprung disease, cardiac defects and autonomic dysfunction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-21233587-A-G is Benign according to our data. Variant chr1-21233587-A-G is described in ClinVar as [Benign]. Clinvar id is 258085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECE1	NM_001397.3	c.1641T>C	p.Asp547=	synonymous_variant	14/19	ENST00000374893.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECE1	ENST00000374893.11	c.1641T>C	p.Asp547=	synonymous_variant	14/19	1	NM_001397.3

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20682 AN: 151976 Hom.: 3171 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0701

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.0589 AC: 14805 AN: 251410 Hom.: 1399 AF XY: 0.0519 AC XY: 7056 AN XY: 135904

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.0362

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.00310

Gnomad SAS exome AF: 0.0229

Gnomad FIN exome AF: 0.0664

Gnomad NFE exome AF: 0.0387

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0460 AC: 67243 AN: 1461460 Hom.: 3819 Cov.: 31 AF XY: 0.0443 AC XY: 32228 AN XY: 727030

Gnomad4 AFR exome AF: 0.390

Gnomad4 AMR exome AF: 0.0396

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.0234

Gnomad4 FIN exome AF: 0.0625

Gnomad4 NFE exome AF: 0.0376

Gnomad4 OTH exome AF: 0.0620

GnomAD4 genome AF: 0.136 AC: 20742 AN: 152094 Hom.: 3183 Cov.: 32 AF XY: 0.134 AC XY: 9950 AN XY: 74366

Gnomad4 AFR AF: 0.381

Gnomad4 AMR AF: 0.0700

Gnomad4 ASJ AF: 0.0447

Gnomad4 EAS AF: 0.00426

Gnomad4 SAS AF: 0.0272

Gnomad4 FIN AF: 0.0662

Gnomad4 NFE AF: 0.0376

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0599 Hom.: 811

Bravo AF: 0.148

Asia WGS AF: 0.0510 AC: 177 AN: 3478

EpiCase AF: 0.0382

EpiControl AF: 0.0378

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.4
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2228321; hg19: chr1-21560080;