2-232483452-C-T

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

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.91
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]

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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
ECEL1NM_004826.4 linkc.1470G>A p.Trp490* stop_gained Exon 8 of 18 ENST00000304546.6 NP_004817.2 O95672-1A0A6F7YIA8
ECEL1NM_001290787.2 linkc.1470G>A p.Trp490* stop_gained Exon 8 of 18 NP_001277716.1 O95672-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ECEL1ENST00000304546.6 linkc.1470G>A p.Trp490* stop_gained Exon 8 of 18 1 NM_004826.4 ENSP00000302051.1 O95672-1
ECEL1ENST00000409941.1 linkc.1470G>A p.Trp490* stop_gained Exon 7 of 17 1 ENSP00000386333.1 O95672-2
ECEL1ENST00000482346.1 linkn.1781G>A non_coding_transcript_exon_variant Exon 7 of 17 2

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000360
AC:
9
AN:
249870
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135178
show subpopulations
Gnomad AFR exome
AF:
0.000494
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.0000130
AC:
19
AN:
1460216
Hom.:
0
Cov.:
32
AF XY:
0.00000964
AC XY:
7
AN XY:
726466
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152338
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000188
Hom.:
0
Bravo
AF:
0.000212
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

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 submitterclinical testingPathology and Clinical Laboratory Medicine, King Fahad Medical City-- -
Pathogenic, no assertion criteria providedclinical testingBaylor GeneticsSep 29, 2014Our 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 14, 2022The 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 submitterclinical testingDASAJan 05, 2022The 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 providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityFeb 05, 2020- -
Pathogenic, criteria provided, single submitterresearchGenomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research CentreMar 17, 2024- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Lab, CHRU Brest-- -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 09, 2022Nonsense 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 providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinJun 11, 2019ACMG classification criteria: PVS1, PM1, PP5, BS1 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
48
DANN
Uncertain
1.0
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.98
D
Vest4
0.83
GERP RS
4.3

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.

Other links and lift over

dbSNP: rs149459910; hg19: chr2-233348162; COSMIC: COSV58814668; COSMIC: COSV58814668; API