rs1190429

Positions:

• chr2-232482880-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004826.4(ECEL1):​c.1656G>A​(p.Lys552=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,614,200 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (32 hom.)
• Consequence: ECEL1 NM_004826.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.29

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-232482880-C-T is Benign according to our data. Variant chr2-232482880-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232482880-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0044 (671/152404) while in subpopulation NFE AF= 0.00707 (481/68048). AF 95% confidence interval is 0.00655. There are 1 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECEL1	NM_004826.4	c.1656G>A	p.Lys552=	synonymous_variant	10/18	ENST00000304546.6
ECEL1	NM_001290787.2	c.1656G>A	p.Lys552=	synonymous_variant	10/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6	c.1656G>A	p.Lys552=	synonymous_variant	10/18	1	NM_004826.4	P4
ECEL1	ENST00000409941.1	c.1656G>A	p.Lys552=	synonymous_variant	9/17	1		A1
ECEL1	ENST00000482346.1	n.1967G>A		non_coding_transcript_exon_variant	9/17	2

Frequencies

GnomAD3 genomes AF: 0.00441 AC: 671 AN: 152286 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00357 AC: 898 AN: 251410 Hom.: 6 AF XY: 0.00372 AC XY: 505 AN XY: 135914

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00606 AC: 8852 AN: 1461796 Hom.: 32 Cov.: 33 AF XY: 0.00582 AC XY: 4233 AN XY: 727204

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00169

Gnomad4 NFE exome AF: 0.00737

Gnomad4 OTH exome AF: 0.00555

GnomAD4 genome AF: 0.00440 AC: 671 AN: 152404 Hom.: 1 Cov.: 33 AF XY: 0.00404 AC XY: 301 AN XY: 74530

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00707

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00522 Hom.: 2

Bravo AF: 0.00490

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ECEL1: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2015	- -

ECEL1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1190429; hg19: chr2-233347590;