2-232481123-C-T

Position:

chr2-232481123-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_004826.4(ECEL1):c.2023G>A(p.Ala675Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000637 in 1,568,684 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

ECEL1
NM_004826.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.54

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:

ECEL1 (HGNC:):

ECEL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 2-232481123-C-T is Pathogenic according to our data. Variant chr2-232481123-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232481123-C-T is described in Lovd as [Pathogenic]. Variant chr2-232481123-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECEL1	NM_004826.4 linkuse as main transcript	c.2023G>A	p.Ala675Thr	missense_variant	15/18	ENST00000304546.6	NP_004817.2	O95672-1A0A6F7YIA8
ECEL1	NM_001290787.2 linkuse as main transcript	c.2017G>A	p.Ala673Thr	missense_variant	15/18		NP_001277716.1	O95672-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ECEL1	ENST00000304546.6 linkuse as main transcript	c.2023G>A	p.Ala675Thr	missense_variant	15/18	1	NM_004826.4	ENSP00000302051.1	O95672-1
ECEL1	ENST00000409941.1 linkuse as main transcript	c.2017G>A	p.Ala673Thr	missense_variant	14/17	1		ENSP00000386333.1	O95672-2
ECEL1	ENST00000411860.5 linkuse as main transcript	c.235-310G>A		intron_variant		3		ENSP00000412683.1	H7C3M0
ECEL1	ENST00000482346.1 linkuse as main transcript	n.2334G>A		non_coding_transcript_exon_variant	14/17	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181008

Hom.:

AF XY:

0.0000104

AC XY:

AN XY:

96568

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000734

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000208

GnomAD4 exome

AF:

0.00000635

AC:

AN:

1416440

Hom.:

Cov.:

AF XY:

0.00000999

AC XY:

AN XY:

700362

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000807

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000459

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Distal arthrogryposis type 5D

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	Predictions from Hansa (Disease causing), PolyPhen-II (Score: 0.99; Probably damaging), and SIFT (Score: 0; Damaging) unanimously indicate that the A675T mutation is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2014	- -
Likely pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2025

Not observed at significant frequency in large population cohorts (gnomAD); 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: 25708584, 25099528, 26752647, 30131190, 30357652, 33672664, 33820833, 33249554) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.93

Loss of stability (P = 0.0203);.;

MVP

0.94

MPC

0.61

ClinPred

1.0

GERP RS

5.8

Varity_R

0.89

gMVP

0.84

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

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