2-232484900-G-C

Variant names:

Variant summary

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

The NM_004826.4(ECEL1):c.967-7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,613,230 control chromosomes in the GnomAD database, including 155 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 12 hom., cov: 34)

Exomes 𝑓: 0.013 ( 143 hom. )

Consequence

ECEL1
NM_004826.4 splice_region, intron

Scores

Splicing: ADA: 0.01538

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0240

Publications

2 publications found

Variant links:

Genes affected

ECEL1 (HGNC:3147): (endothelin converting enzyme like 1) This gene encodes a member of the M13 family of endopeptidases. Members of this family are zinc-containing type II integral-membrane proteins that are important regulators of neuropeptide and peptide hormone activity. Mutations in this gene are associated with autosomal recessive distal arthrogryposis, type 5D. This gene has multiple pseudogenes on chromosome 2. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

ECEL1 Gene-Disease associations (from GenCC):

distal arthrogryposis type 5D
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ECEL1 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=-0.82).

BP6

Variant 2-232484900-G-C is Benign according to our data. Variant chr2-232484900-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128956.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 = 0.0088 (1341/152318) while in subpopulation NFE AF = 0.0142 (964/68016). AF 95% confidence interval is 0.0134. There are 12 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4 link	c.967-7C>G		splice_region_variant, intron_variant	Intron 4 of 17	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2 link	c.967-7C>G		splice_region_variant, intron_variant	Intron 4 of 17		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ECEL1	ENST00000304546.6 link	c.967-7C>G	splice_region_variant, intron_variant	Intron 4 of 17	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1 link	c.967-7C>G	splice_region_variant, intron_variant	Intron 3 of 16	1		ENSP00000386333.1
ECEL1	ENST00000482346.1 link	n.1278-7C>G	splice_region_variant, intron_variant	Intron 3 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.00880

AC:

1340

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0147

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00876

AC:

2196

AN:

250802

AF XY:

0.00865

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00443

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0135

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0128

AC:

18701

AN:

1460912

Hom.:

143

Cov.:

AF XY:

0.0124

AC XY:

9006

AN XY:

726782

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33478

American (AMR)

AF:

0.00463

AC:

207

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00232

AC:

200

AN:

86250

European-Finnish (FIN)

AF:

0.0148

AC:

780

AN:

52664

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0151

AC:

16801

AN:

1111820

Other (OTH)

AF:

0.0101

AC:

607

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1068

2136

3203

4271

5339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

624

1248

1872

2496

3120

<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:

0.00880

AC:

1341

AN:

152318

Hom.:

Cov.:

AF XY:

0.00863

AC XY:

643

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00245

AC:

102

AN:

41562

American (AMR)

AF:

0.00627

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00228

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0147

AC:

156

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0142

AC:

964

AN:

68016

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

146

220

293

366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0105

Hom.:

Bravo

AF:

0.00829

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0116

EpiControl

AF:

0.0116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 01, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ECEL1: BP4, BS1, BS2

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 06, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.1

(source)

DANN

Benign

0.42

PhyloP100

-0.024

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.015

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.010

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