2-232486228-G-T

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.426C>A(p.Asp142Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,601,354 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 9 hom., cov: 34)

Exomes 𝑓: 0.010 ( 110 hom. )

Consequence

ECEL1
NM_004826.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.17

Publications

7 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 (MetaRNN=0.008290321).

BP6

Variant 2-232486228-G-T is Benign according to our data. Variant chr2-232486228-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128954.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 = 0.00873 (1330/152328) while in subpopulation NFE AF = 0.0127 (867/68024). AF 95% confidence interval is 0.012. There are 9 homozygotes in GnomAd4. There are 688 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4 link	c.426C>A	p.Asp142Glu	missense_variant	Exon 2 of 18	ENST00000304546.6	NP_004817.2	O95672-1A0A6F7YIA8
ECEL1	NM_001290787.2 link	c.426C>A	p.Asp142Glu	missense_variant	Exon 2 of 18		NP_001277716.1	O95672-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ECEL1	ENST00000304546.6 link	c.426C>A	p.Asp142Glu	missense_variant	Exon 2 of 18	1	NM_004826.4	ENSP00000302051.1	O95672-1
ECEL1	ENST00000409941.1 link	c.426C>A	p.Asp142Glu	missense_variant	Exon 1 of 17	1		ENSP00000386333.1	O95672-2
ECEL1	ENST00000482346.1 link	n.630C>A		non_coding_transcript_exon_variant	Exon 2 of 17	2

Frequencies

GnomAD3 genomes

AF:

0.00873

AC:

1329

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00942

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00798

AC:

1802

AN:

225814

AF XY:

0.00782

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.00702

Gnomad ASJ exome

AF:

0.00241

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0104

AC:

15082

AN:

1449026

Hom.:

110

Cov.:

AF XY:

0.0102

AC XY:

7373

AN XY:

721226

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

32774

American (AMR)

AF:

0.00656

AC:

292

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00246

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39358

South Asian (SAS)

AF:

0.000466

AC:

AN:

85890

European-Finnish (FIN)

AF:

0.0172

AC:

787

AN:

45674

Middle Eastern (MID)

AF:

0.00644

AC:

AN:

4500

European-Non Finnish (NFE)

AF:

0.0121

AC:

13381

AN:

1110398

Other (OTH)

AF:

0.00729

AC:

437

AN:

59908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1070

2141

3211

4282

5352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.00873

AC:

1330

AN:

152328

Hom.:

Cov.:

AF XY:

0.00924

AC XY:

688

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

41584

American (AMR)

AF:

0.00947

AC:

145

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00103

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0185

AC:

196

AN:

10620

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0127

AC:

867

AN:

68024

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

144

215

287

359

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:

0.00668

Hom.:

Bravo

AF:

0.00747

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00206

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00801

AC:

959

Asia WGS

AF:

0.000868

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Oct 19, 2020

GeneDx

Significance:Likely 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

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ECEL1: BS1, BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 07, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0083

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

N;N

PhyloP100

1.2

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.15

Sift

Benign

0.34

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.054

MutPred

0.41

Loss of catalytic residue at D142 (P = 0.2468);Loss of catalytic residue at D142 (P = 0.2468);

MVP

0.46

MPC

0.95

ClinPred

0.018

GERP RS

2.0

PromoterAI

0.0048

Neutral

(source)

Varity_R

0.075

gMVP

0.19

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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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