2-232486064-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_004826.4(ECEL1):c.590G>A(p.Gly197Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,605,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G197S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ECEL1
NM_004826.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.85

Publications

4 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-232486065-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3340601.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4 link	c.590G>A	p.Gly197Asp	missense_variant	Exon 2 of 18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2 link	c.590G>A	p.Gly197Asp	missense_variant	Exon 2 of 18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ECEL1	ENST00000304546.6 link	c.590G>A	p.Gly197Asp	missense_variant	Exon 2 of 18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1 link	c.590G>A	p.Gly197Asp	missense_variant	Exon 1 of 17	1		ENSP00000386333.1
ECEL1	ENST00000482346.1 link	n.794G>A		non_coding_transcript_exon_variant	Exon 2 of 17	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

225142

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000963

AC:

AN:

1453422

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

722642

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33318

American (AMR)

AF:

0.00

AC:

AN:

44088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25942

East Asian (EAS)

AF:

0.00

AC:

AN:

39436

South Asian (SAS)

AF:

0.00

AC:

AN:

85270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1109232

Other (OTH)

AF:

0.00

AC:

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000712

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Distal arthrogryposis type 5D

Pathogenic:1

Jan 10, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Oct 31, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with clinical features consistent with distal arthrogryposis 5D in published literature (McMillin et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25173900, 25708584, 23261301) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.036

MutationAssessor

Benign

1.6

L;L

PhyloP100

5.8

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.070

T;T

Polyphen

0.97

D;D

Vest4

0.85

MutPred

0.66

Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);

MVP

0.88

MPC

0.70

ClinPred

0.99

GERP RS

4.1

Varity_R

0.82

gMVP

0.92

Mutation Taster

=21/79

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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