rs1341894581

Positions:

• chr2-232486498-CAGCCCGGACCGGGCCCCGGTGGCGCTGCGCGCAGCGCCCAACGGGA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004826.4(ECEL1):​c.110_155del​(p.Phe37CysfsTer151) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000571 in 1,383,780 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000051 (0 hom.)
• Consequence: ECEL1 NM_004826.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.70

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]

ACMG classification

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 2-232486498-CAGCCCGGACCGGGCCCCGGTGGCGCTGCGCGCAGCGCCCAACGGGA-C is Pathogenic according to our data. Variant chr2-232486498-CAGCCCGGACCGGGCCCCGGTGGCGCTGCGCGCAGCGCCCAACGGGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 435024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232486498-CAGCCCGGACCGGGCCCCGGTGGCGCTGCGCGCAGCGCCCAACGGGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECEL1	NM_004826.4	c.110_155del	p.Phe37CysfsTer151	frameshift_variant	2/18	ENST00000304546.6
ECEL1	NM_001290787.2	c.110_155del	p.Phe37CysfsTer151	frameshift_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6	c.110_155del	p.Phe37CysfsTer151	frameshift_variant	2/18	1	NM_004826.4	P4
ECEL1	ENST00000409941.1	c.110_155del	p.Phe37CysfsTer151	frameshift_variant	1/17	1		A1
ECEL1	ENST00000482346.1	n.314_359del		non_coding_transcript_exon_variant	2/17	2

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 151644 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000326 AC: 7 AN: 21450 Hom.: 0 AF XY: 0.000299 AC XY: 4 AN XY: 13386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00195

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: 0.000215

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000511 AC: 63 AN: 1232136 Hom.: 0 AF XY: 0.0000431 AC XY: 26 AN XY: 602972

Gnomad4 AFR exome AF: 0.0000417

Gnomad4 AMR exome AF: 0.000750

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000367

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000494

Gnomad4 OTH exome AF: 0.0000395

GnomAD4 genome AF: 0.000106 AC: 16 AN: 151644 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 12 AN XY: 74044

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000737

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000253 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal arthrogryposis type 5D Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Aug 15, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with distal arthrogryposis, type 5D (MIM#615065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3) for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are multiple NMD-predicted variants that have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been identified in individuals with distal arthrogryposis (ClinVar; PMIDs: 30792901, 33966749, 33060286). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a heterozygous likely pathogenic variant, NM_004826.3(ECEL1):c.1783_1788del, p.(Pro595Asp596del), in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 05, 2016	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2022

Identified in the presence of a second ECEL1 variant in a patient with arthrogryposis (Scocchia et al., 2019); Frameshift 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: 23236030, 23261301, 25099528, 24782201, 25708584, 33743358, 33966749, 30792901, 27535533) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1341894581; hg19: chr2-233351208;