Genetic Variant ECE1:c.2040+129C>T (chr1-21225121-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001397.3(ECE1):c.2040+129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,266,276 control chromosomes in the GnomAD database, including 768 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.027 ( 86 hom., cov: 32)

Exomes 𝑓: 0.032 ( 682 hom. )

Consequence

ECE1
NM_001397.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.59

Publications

1 publications found

Variant links:

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)

ECE1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0273 (4154/152270) while in subpopulation NFE AF = 0.0342 (2326/68020). AF 95% confidence interval is 0.033. There are 86 homozygotes in GnomAd4. There are 2104 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 86 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3 link	c.2040+129C>T		intron_variant	Intron 17 of 18	ENST00000374893.11	NP_001388.1	P42892-1A1PUP8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11 link	c.2040+129C>T		intron_variant	Intron 17 of 18	1	NM_001397.3	ENSP00000364028.6		P42892-1

Frequencies

GnomAD3 genomes

AF:

0.0273

AC:

4155

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.0378

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.0663

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0342

Gnomad OTH

AF:

0.0264

GnomAD4 exome

AF:

0.0322

AC:

35878

AN:

1114006

Hom.:

682

AF XY:

0.0316

AC XY:

17549

AN XY:

555062

show subpopulations

African (AFR)

AF:

0.0102

AC:

271

AN:

26496

American (AMR)

AF:

0.0141

AC:

463

AN:

32774

Ashkenazi Jewish (ASJ)

AF:

0.0342

AC:

668

AN:

19530

East Asian (EAS)

AF:

0.0000272

AC:

AN:

36748

South Asian (SAS)

AF:

0.0136

AC:

918

AN:

67670

European-Finnish (FIN)

AF:

0.0609

AC:

2144

AN:

35184

Middle Eastern (MID)

AF:

0.0306

AC:

102

AN:

3338

European-Non Finnish (NFE)

AF:

0.0353

AC:

29812

AN:

843828

Other (OTH)

AF:

0.0309

AC:

1499

AN:

48438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1697

3394

5092

6789

8486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0273

AC:

4154

AN:

152270

Hom.:

Cov.:

AF XY:

0.0283

AC XY:

2104

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0119

AC:

493

AN:

41566

American (AMR)

AF:

0.0228

AC:

349

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0378

AC:

131

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0122

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0663

AC:

703

AN:

10608

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0342

AC:

2326

AN:

68020

Other (OTH)

AF:

0.0261

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

197

394

590

787

984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0306

Hom.:

Bravo

AF:

0.0240

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.12

(source)

DANN

Benign

0.77

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism

(source)

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

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chr1-21225121-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over