2-232484472-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_004826.4(ECEL1):c.1184G>A(p.Arg395Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,461,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ECEL1
NM_004826.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.68

Publications

5 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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-232484472-C-T is Pathogenic according to our data. Variant chr2-232484472-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 235819.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.1184G>A	p.Arg395Gln	missense_variant, splice_region_variant	Exon 6 of 18	ENST00000304546.6	NP_004817.2	O95672-1A0A6F7YIA8
ECEL1	NM_001290787.2 link	c.1184G>A	p.Arg395Gln	missense_variant, splice_region_variant	Exon 6 of 18		NP_001277716.1	O95672-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ECEL1	ENST00000304546.6 link	c.1184G>A	p.Arg395Gln	missense_variant, splice_region_variant	Exon 6 of 18	1	NM_004826.4	ENSP00000302051.1	O95672-1
ECEL1	ENST00000409941.1 link	c.1184G>A	p.Arg395Gln	missense_variant, splice_region_variant	Exon 5 of 17	1		ENSP00000386333.1	O95672-2
ECEL1	ENST00000482346.1 link	n.1495G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 17	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461240

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111742

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Distal arthrogryposis type 5D

Pathogenic:2

Oct 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ECEL1 c.1184G>A (p.Arg395Gln) results in a conservative amino acid change located in the Peptidase M13, N-terminal domain (IPR008753) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant significantly weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251240 control chromosomes. c.1184G>A has been reported in the literature in two unrelated homozygous individuals affected with Distal Arthrogryposis Type 5D/arthrogryposis multiplex congenita (McMillin2013, Laquerriere_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38568023, 33820833, 23261301). ClinVar contains an entry for this variant (Variation ID: 235819). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jan 08, 2013

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

3.7

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.11

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.95

P;P

Vest4

0.85

MutPred

0.46

Loss of MoRF binding (P = 0.0164);Loss of MoRF binding (P = 0.0164);

MVP

0.80

MPC

0.52

ClinPred

0.95

GERP RS

4.8

Varity_R

0.36

gMVP

0.63

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.64

Position offset: -42

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over