rs2228321

Variant names:

• chr1-21233587-A-G
• rs2228321
• NM_001397.3:c.1641T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001397.3(ECE1):​c.1641T>C​(p.Asp547Asp) 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
• Publications: 5 publications found

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]

ECE1 Gene-Disease associations (from GenCC):

• essential hypertension, genetic

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ECE1	NM_001397.3	c.1641T>C	p.Asp547Asp	synonymous_variant	Exon 14 of 19	ENST00000374893.11	NP_001388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11	c.1641T>C	p.Asp547Asp	synonymous_variant	Exon 14 of 19	1	NM_001397.3	ENSP00000364028.6

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

GnomAD2 exomes AF: 0.0589 AC: 14805 AN: 251410 AF XY: 0.0519

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 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

African (AFR) AF: 0.390 AC: 13050 AN: 33462

American (AMR) AF: 0.0396 AC: 1769 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 1061 AN: 26136

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39696

South Asian (SAS) AF: 0.0234 AC: 2014 AN: 86244

European-Finnish (FIN) AF: 0.0625 AC: 3338 AN: 53410

Middle Eastern (MID) AF: 0.0668 AC: 370 AN: 5536

European-Non Finnish (NFE) AF: 0.0376 AC: 41832 AN: 1111904

Other (OTH) AF: 0.0620 AC: 3742 AN: 60350

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

African (AFR) AF: 0.381 AC: 15814 AN: 41454

American (AMR) AF: 0.0700 AC: 1069 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3468

East Asian (EAS) AF: 0.00426 AC: 22 AN: 5166

South Asian (SAS) AF: 0.0272 AC: 131 AN: 4822

European-Finnish (FIN) AF: 0.0662 AC: 701 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2556 AN: 67996

Other (OTH) AF: 0.117 AC: 246 AN: 2108

Alfa AF: 0.0715 Hom.: 1397

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

Nov 12, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.4
DANN	Benign	0.59
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2228321; hg19: chr1-21560080;