rs765305996

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_004826.4(ECEL1):c.494T>C(p.Leu165Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000984 in 1,422,786 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

ECEL1
NM_004826.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 4.49

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 2-232486160-A-G is Pathogenic according to our data. Variant chr2-232486160-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521056.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4 link	c.494T>C	p.Leu165Pro	missense_variant	Exon 2 of 18	ENST00000304546.6	NP_004817.2	O95672-1A0A6F7YIA8
ECEL1	NM_001290787.2 link	c.494T>C	p.Leu165Pro	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.494T>C	p.Leu165Pro	missense_variant	Exon 2 of 18	1	NM_004826.4	ENSP00000302051.1	O95672-1
ECEL1	ENST00000409941.1 link	c.494T>C	p.Leu165Pro	missense_variant	Exon 1 of 17	1		ENSP00000386333.1	O95672-2
ECEL1	ENST00000482346.1 link	n.698T>C		non_coding_transcript_exon_variant	Exon 2 of 17	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000382

AC:

AN:

183120

Hom.:

AF XY:

0.0000684

AC XY:

AN XY:

102392

show subpopulations

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 SAS exome

AF:

0.000269

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000984

AC:

AN:

1422786

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

705920

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000158

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000259

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Distal arthrogryposis type 5D

Uncertain:2

Aug 06, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2020

Centogene AG - the Rare Disease Company

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Nov 16, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.494T>C (p.L165P) alteration is located in exon 2 (coding exon 1) of the ECEL1 gene. This alteration results from a T to C substitution at nucleotide position 494, causing the leucine (L) at amino acid position 165 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD) database, the ECEL1 c.494T>C alteration was observed in 0.004% (7/183120) of total alleles studied, with a frequency of 0.03% (7/25980) in the South Asian subpopulation. This alteration has been detected in the homozygous state multiple patients with a clinical phenotype consistent with ECEL1-related multiple congenital contractures (Ambry internal data; North Thames Genomic Laboratory Hub personal communication). In addition, this alteration was reported in trans with a second missense variant in a patient with distal arthrogryposis (Lindstrand, 2019). This amino acid position is conserved in available mammalian species. The p.L165P alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Jan 10, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25099528, 37273706, 25708584, 24782201, 23261301, 23236030, 34940998, 30919572, 33726816, 36002593, 31694722) -

Arthrogryposis multiplex congenita

Uncertain:1

Apr 09, 2019

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.69

T;T

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.41

B;D

Vest4

0.61

MutPred

0.86

Gain of disorder (P = 0.0166);Gain of disorder (P = 0.0166);

MVP

0.82

MPC

2.7

ClinPred

0.89

GERP RS

3.9

Varity_R

0.98

gMVP

0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over