2-232486228-G-T

Position:

chr2-232486228-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004826.4(ECEL1):c.426C>A(p.Asp142Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,601,354 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 9 hom., cov: 34)

Exomes 𝑓: 0.010 ( 110 hom. )

Consequence

ECEL1
NM_004826.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008290321).

BP6

Variant 2-232486228-G-T is Benign according to our data. Variant chr2-232486228-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 128954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232486228-G-T is described in Lovd as [Benign]. Variant chr2-232486228-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00873 (1330/152328) while in subpopulation NFE AF= 0.0127 (867/68024). AF 95% confidence interval is 0.012. There are 9 homozygotes in gnomad4. There are 688 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECEL1	NM_004826.4 linkuse as main transcript	c.426C>A	p.Asp142Glu	missense_variant	2/18	ENST00000304546.6
ECEL1	NM_001290787.2 linkuse as main transcript	c.426C>A	p.Asp142Glu	missense_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6 linkuse as main transcript	c.426C>A	p.Asp142Glu	missense_variant	2/18	1	NM_004826.4	P4	O95672-1
ECEL1	ENST00000409941.1 linkuse as main transcript	c.426C>A	p.Asp142Glu	missense_variant	1/17	1		A1	O95672-2
ECEL1	ENST00000482346.1 linkuse as main transcript	n.630C>A		non_coding_transcript_exon_variant	2/17	2

Frequencies

GnomAD3 genomes

AF:

0.00873

AC:

1329

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00942

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00798

AC:

1802

AN:

225814

Hom.:

AF XY:

0.00782

AC XY:

982

AN XY:

125558

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.00702

Gnomad ASJ exome

AF:

0.00241

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000366

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0104

AC:

15082

AN:

1449026

Hom.:

110

Cov.:

AF XY:

0.0102

AC XY:

7373

AN XY:

721226

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.00656

Gnomad4 ASJ exome

AF:

0.00246

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000466

Gnomad4 FIN exome

AF:

0.0172

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00729

GnomAD4 genome

AF:

0.00873

AC:

1330

AN:

152328

Hom.:

Cov.:

AF XY:

0.00924

AC XY:

688

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00947

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.0185

Gnomad4 NFE

AF:

0.0127

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.00743

Hom.:

Bravo

AF:

0.00747

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00206

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00801

AC:

959

Asia WGS

AF:

0.000868

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ECEL1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0083

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

N;N

MutationTaster

Benign

0.90

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.15

Sift

Benign

0.34

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.054

MutPred

0.41

Loss of catalytic residue at D142 (P = 0.2468);Loss of catalytic residue at D142 (P = 0.2468);

MVP

0.46

MPC

0.95

ClinPred

0.018

GERP RS

2.0

Varity_R

0.075

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over