2-232486144-AC-A

Position:

• chr2-232486144-AC-A

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.509del​(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

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 2-232486144-AC-A is Pathogenic according to our data. Variant chr2-232486144-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 435023.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.509del	p.Gly170ValfsTer33	frameshift_variant	2/18	ENST00000304546.6
ECEL1	NM_001290787.2	c.509del	p.Gly170ValfsTer33	frameshift_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6	c.509del	p.Gly170ValfsTer33	frameshift_variant	2/18	1	NM_004826.4	P4
ECEL1	ENST00000409941.1	c.509del	p.Gly170ValfsTer33	frameshift_variant	1/17	1		A1
ECEL1	ENST00000482346.1	n.713del		non_coding_transcript_exon_variant	2/17	2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000408

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.17e-7

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Dec 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 04, 2016	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553567937; hg19: chr2-233350854;