2-232483452-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004826.4(ECEL1):c.1470G>A(p.Trp490*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,612,554 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
ECEL1
NM_004826.4 stop_gained
NM_004826.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 7.91
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-232483452-C-T is Pathogenic according to our data. Variant chr2-232483452-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 374305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232483452-C-T is described in Lovd as [Pathogenic]. Variant chr2-232483452-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ECEL1 | NM_004826.4 | c.1470G>A | p.Trp490* | stop_gained | Exon 8 of 18 | ENST00000304546.6 | NP_004817.2 | |
ECEL1 | NM_001290787.2 | c.1470G>A | p.Trp490* | stop_gained | Exon 8 of 18 | NP_001277716.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ECEL1 | ENST00000304546.6 | c.1470G>A | p.Trp490* | stop_gained | Exon 8 of 18 | 1 | NM_004826.4 | ENSP00000302051.1 | ||
ECEL1 | ENST00000409941.1 | c.1470G>A | p.Trp490* | stop_gained | Exon 7 of 17 | 1 | ENSP00000386333.1 | |||
ECEL1 | ENST00000482346.1 | n.1781G>A | non_coding_transcript_exon_variant | Exon 7 of 17 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152220Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000360 AC: 9AN: 249870Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135178
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152338Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74490
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Distal arthrogryposis type 5D Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Sep 29, 2014 | Our laboratory reported dual molecular diagnoses in ARHGEF10 (NM_014629.2, c.1456dup and c.2063G>A in trans) and ECEL1 (NM_004826.2, c.1470G>A) in this individual reported to have features of delayed motor milestones, dysmorphic features, joint contracture at elbow, knee and small joints and camptodactyly. Compound heterozygous pathogenic variants including c.1470G>A (p.W490X) have been previously reported in a patient with recessive form of distal arthrogryposis (PMID 23236030). Heterozygotes for this variant would be expected to be asymptomatic carriers. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 14, 2022 | The ECEL1 c.1470G>A; p.Trp490Ter variant (rs149459910) is reported in the literature in the compound heterozygous and homozygous states in individuals with distal arthrogryposis (AlBanji 2020, Dieterich 2013, Posey 2017). This variant is found in the African/African-American population with an allele frequency of 0.048% (12/24910 alleles) in the Genome Aggregation Database ; it is also reported in ClinVar (Variation ID: 374305). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: AlBanji MH et al. Utility of Hypotonia Diagnostic Investigations: A 12-year Single Center Study. Mol Genet Metab Rep. 2020 Oct 21;25:100665. PMID: 33101984 Dieterich K et al. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis. Hum Mol Genet. 2013 Apr 15;22(8):1483-92. PMID: 23236030. Posey JE et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017 Jan 5;376(1):21-31. PMID: 27959697 - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.1470G>A;p.(Trp490*) variant creates a premature translational stop signal in the ECEL1 gene. It is expected to result in an absent or disrupted protein product - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 374305; PMID: 23236030) - PS4_moderate. The variant is present at low allele frequencies population databases (rs149459910 – gnomAD 0.01117%; ABraOM no frequency- http://abraom.ib.usp.br/) -PM2_supporting. The p.(Trp490*) was detected in trans with a pathogenic variant (PMID: 23236030) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Feb 05, 2020 | - - |
Pathogenic, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Lab, CHRU Brest | - | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27959697, 33491998, 23236030, 30131190, 31127727, 33101984, 33672664) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jun 11, 2019 | ACMG classification criteria: PVS1, PM1, PP5, BS1 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at