dbSNP rs1553567937: ECEL1:p.Gly170ValfsTer33 (chr2-232486144-AC-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.60

Publications

1 publications found

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]

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

ECEL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4 link	c.509delG	p.Gly170ValfsTer33	frameshift_variant	Exon 2 of 18	ENST00000304546.6	NP_004817.2	O95672-1A0A6F7YIA8
ECEL1	NM_001290787.2 link	c.509delG	p.Gly170ValfsTer33	frameshift_variant	Exon 2 of 18		NP_001277716.1	O95672-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ECEL1	ENST00000304546.6 link	c.509delG	p.Gly170ValfsTer33	frameshift_variant	Exon 2 of 18	1	NM_004826.4	ENSP00000302051.1	O95672-1
ECEL1	ENST00000409941.1 link	c.509delG	p.Gly170ValfsTer33	frameshift_variant	Exon 1 of 17	1		ENSP00000386333.1	O95672-2
ECEL1	ENST00000482346.1 link	n.713delG		non_coding_transcript_exon_variant	Exon 2 of 17	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1407450

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

697254

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31286

American (AMR)

AF:

0.00

AC:

AN:

36562

Ashkenazi Jewish (ASJ)

AF:

0.0000408

AC:

AN:

24500

East Asian (EAS)

AF:

0.00

AC:

AN:

37464

South Asian (SAS)

AF:

0.00

AC:

AN:

80324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5328

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090918

Other (OTH)

AF:

0.00

AC:

AN:

58300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.6

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over