rs765305996

Positions:

• chr2-232486160-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004826.4(ECEL1):​c.494T>C​(p.Leu165Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000984 in 1,422,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 4.49

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 2-232486160-A-G is Pathogenic according to our data. Variant chr2-232486160-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521056.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.494T>C	p.Leu165Pro	missense_variant	2/18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.494T>C	p.Leu165Pro	missense_variant	2/18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.494T>C	p.Leu165Pro	missense_variant	2/18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.494T>C	p.Leu165Pro	missense_variant	1/17	1		ENSP00000386333.1
ECEL1	ENST00000482346.1	n.698T>C		non_coding_transcript_exon_variant	2/17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000382 AC: 7 AN: 183120 Hom.: 0 AF XY: 0.0000684 AC XY: 7 AN XY: 102392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000269

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000984 AC: 14 AN: 1422786 Hom.: 0 Cov.: 32 AF XY: 0.0000156 AC XY: 11 AN XY: 705920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000259 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Distal arthrogryposis type 5D Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 27, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 06, 2020	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2020

The c.494T>C (p.L165P) alteration is located in exon 2 (coding exon 1) of the ECEL1 gene. This alteration results from a T to C substitution at nucleotide position 494, causing the leucine (L) at amino acid position 165 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD) database, the ECEL1 c.494T>C alteration was observed in 0.004% (7/183120) of total alleles studied, with a frequency of 0.03% (7/25980) in the South Asian subpopulation. This alteration has been detected in the homozygous state multiple patients with a clinical phenotype consistent with ECEL1-related multiple congenital contractures (Ambry internal data; North Thames Genomic Laboratory Hub personal communication). In addition, this alteration was reported in trans with a second missense variant in a patient with distal arthrogryposis (Lindstrand, 2019). This amino acid position is conserved in available mammalian species. The p.L165P alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2025

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25099528, 37273706, 25708584, 24782201, 23261301, 23236030, 34940998, 30919572, 33726816, 36002593, 31694722) -

Arthrogryposis multiplex congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Apr 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.41	B;D
Vest4		0.61
MutPred		0.86		Gain of disorder (P = 0.0166);Gain of disorder (P = 0.0166);
MVP		0.82
MPC		2.7
ClinPred		0.89	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs765305996; hg19: chr2-233350870;