rs587777129

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_004826.4(ECEL1):c.2278T>C(p.Cys760Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C760F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ECEL1
NM_004826.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.75

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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 2-232480203-A-G is Pathogenic according to our data. Variant chr2-232480203-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 100650.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4 link	c.2278T>C	p.Cys760Arg	missense_variant	Exon 18 of 18	ENST00000304546.6	NP_004817.2	O95672-1A0A6F7YIA8
ECEL1	NM_001290787.2 link	c.2272T>C	p.Cys758Arg	missense_variant	Exon 18 of 18		NP_001277716.1	O95672-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ECEL1	ENST00000304546.6 link	c.2278T>C	p.Cys760Arg	missense_variant	Exon 18 of 18	1	NM_004826.4	ENSP00000302051.1	O95672-1
ECEL1	ENST00000409941.1 link	c.2272T>C	p.Cys758Arg	missense_variant	Exon 17 of 17	1		ENSP00000386333.1	O95672-2
ECEL1	ENST00000411860.5 link	c.457T>C	p.Cys153Arg	missense_variant	Exon 6 of 6	3		ENSP00000412683.1	H7C3M0
ECEL1	ENST00000482346.1 link	n.2589T>C		non_coding_transcript_exon_variant	Exon 17 of 17	2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000551

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Distal arthrogryposis type 5D

Pathogenic:1

Apr 15, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;H;.

PhyloP100

8.8

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-12

D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.97, 0.95

MutPred

0.90

.;Gain of disorder (P = 0.0035);.;

MVP

0.95

MPC

0.83

ClinPred

1.0

GERP RS

5.2

Varity_R

0.99

gMVP

0.93

Mutation Taster

=1/99

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over