rs587776917

Positions:

• chr2-232485937-G-GT

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.716_717insA​(p.Tyr239Ter) variant causes a stop gained, frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ECEL1 NM_004826.4 stop_gained, frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.17

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 2-232485937-G-GT is Pathogenic according to our data. Variant chr2-232485937-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 39488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECEL1	NM_004826.4	c.716_717insA	p.Tyr239Ter	stop_gained, frameshift_variant	2/18	ENST00000304546.6
ECEL1	NM_001290787.2	c.716_717insA	p.Tyr239Ter	stop_gained, frameshift_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6	c.716_717insA	p.Tyr239Ter	stop_gained, frameshift_variant	2/18	1	NM_004826.4	P4
ECEL1	ENST00000409941.1	c.716_717insA	p.Tyr239Ter	stop_gained, frameshift_variant	1/17	1		A1
ECEL1	ENST00000482346.1	n.920_921insA		non_coding_transcript_exon_variant	2/17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal arthrogryposis type 5D Pathogenic:3

Pathogenic, criteria provided, single submitter	research	University of Washington Center for Mendelian Genomics, University of Washington	Jan 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	Sanger sequencing showed a homozygous sequence variant in ECEL1 gene resulting in termination of protein. It is predicted as pathogenic by MutationTaster. This variant is classified as pathogenic which shows strong evidence of pathogenicity according to ACMG guidelines (Richards et al., 2015). Parents were heterozygous for the same variation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 10, 2013	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs587776917; hg19: chr2-233350647;