dbSNP rs28368004: ECE1:c.1278+7C>T (chr1-21244982-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001397.3(ECE1):c.1278+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,612,874 control chromosomes in the GnomAD database, including 966 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 84 hom., cov: 32)

Exomes 𝑓: 0.031 ( 882 hom. )

Consequence

ECE1
NM_001397.3 splice_region, intron

Scores

Splicing: ADA: 0.0002036

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.26

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 1-21244982-G-A is Benign according to our data. Variant chr1-21244982-G-A is described in ClinVar as Benign. ClinVar VariationId is 258082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0238 (3626/152282) while in subpopulation NFE AF = 0.0353 (2401/68016). AF 95% confidence interval is 0.0341. There are 84 homozygotes in GnomAd4. There are 1892 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 84 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3 link	c.1278+7C>T		splice_region_variant, intron_variant	Intron 10 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.1278+7C>T		splice_region_variant, intron_variant	Intron 10 of 18	1	NM_001397.3	ENSP00000364028.6		P42892-1

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3625

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00577

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00766

Gnomad FIN

AF:

0.0592

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0353

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0241

AC:

6054

AN:

251418

AF XY:

0.0244

show subpopulations

Gnomad AFR exome

AF:

0.00615

Gnomad AMR exome

AF:

0.00931

Gnomad ASJ exome

AF:

0.0157

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0619

Gnomad NFE exome

AF:

0.0328

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0313

AC:

45659

AN:

1460592

Hom.:

882

Cov.:

AF XY:

0.0306

AC XY:

22262

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.00463

AC:

155

AN:

33456

American (AMR)

AF:

0.00997

AC:

446

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

408

AN:

26122

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39686

South Asian (SAS)

AF:

0.00813

AC:

701

AN:

86240

European-Finnish (FIN)

AF:

0.0605

AC:

3229

AN:

53398

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0351

AC:

39000

AN:

1110850

Other (OTH)

AF:

0.0274

AC:

1652

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

2189

4379

6568

8758

10947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1428

2856

4284

5712

7140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0238

AC:

3626

AN:

152282

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1892

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00575

AC:

239

AN:

41546

American (AMR)

AF:

0.0131

AC:

201

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00746

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0592

AC:

628

AN:

10606

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0353

AC:

2401

AN:

68016

Other (OTH)

AF:

0.0241

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

180

360

541

721

901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0296

Hom.:

144

Bravo

AF:

0.0195

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0311

EpiControl

AF:

0.0303

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.1

(source)

DANN

Benign

0.67

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.026

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over