chr2-232486144-AC-A

Variant names:

• chr2-232486144-AC-A
• rs1553567937
• NM_004826.4:c.509delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004826.4(ECEL1):​c.509delG​(p.Gly170ValfsTer33) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000142 in 1,407,450 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ECEL1 NM_004826.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.60
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• distal arthrogryposis type 5D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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 2-232486144-AC-A is Pathogenic according to our data. Variant chr2-232486144-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 435023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004826.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	NM_004826.4	MANE Select	c.509delG	p.Gly170ValfsTer33	frameshift	Exon 2 of 18	NP_004817.2
	ECEL1	NM_001290787.2		c.509delG	p.Gly170ValfsTer33	frameshift	Exon 2 of 18	NP_001277716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	ENST00000304546.6	TSL:1 MANE Select	c.509delG	p.Gly170ValfsTer33	frameshift	Exon 2 of 18	ENSP00000302051.1
	ECEL1	ENST00000409941.1	TSL:1	c.509delG	p.Gly170ValfsTer33	frameshift	Exon 1 of 17	ENSP00000386333.1
	ECEL1	ENST00000482346.1	TSL:2	n.713delG		non_coding_transcript_exon	Exon 2 of 17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1407450 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 697254

African (AFR) AF: 0.00 AC: 0 AN: 31286

American (AMR) AF: 0.00 AC: 0 AN: 36562

Ashkenazi Jewish (ASJ) AF: 0.0000408 AC: 1 AN: 24500

East Asian (EAS) AF: 0.00 AC: 0 AN: 37464

South Asian (SAS) AF: 0.00 AC: 0 AN: 80324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5328

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090918

Other (OTH) AF: 0.00 AC: 0 AN: 58300

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal arthrogryposis type 5D Pathogenic:2

Dec 22, 2017

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553567937; hg19: chr2-233350854;