chr2-232484472-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
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 Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
ECEL1
NM_004826.4 missense, splice_region
NM_004826.4 missense, splice_region
Scores
3
6
10
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.68
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius 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]. Clinvar id is 235819.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-232484472-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ECEL1 | NM_004826.4 | c.1184G>A | p.Arg395Gln | missense_variant, splice_region_variant | 6/18 | ENST00000304546.6 | |
ECEL1 | NM_001290787.2 | c.1184G>A | p.Arg395Gln | missense_variant, splice_region_variant | 6/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ECEL1 | ENST00000304546.6 | c.1184G>A | p.Arg395Gln | missense_variant, splice_region_variant | 6/18 | 1 | NM_004826.4 | P4 | |
ECEL1 | ENST00000409941.1 | c.1184G>A | p.Arg395Gln | missense_variant, splice_region_variant | 5/17 | 1 | A1 | ||
ECEL1 | ENST00000482346.1 | n.1495G>A | splice_region_variant, non_coding_transcript_exon_variant | 5/17 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461240Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726880
GnomAD4 exome
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AC:
6
AN:
1461240
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Cov.:
33
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AC XY:
1
AN XY:
726880
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Distal arthrogryposis type 5D Pathogenic:1
Pathogenic, criteria provided, single submitter | research | University of Washington Center for Mendelian Genomics, University of Washington | Jan 08, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;P
Vest4
MutPred
Loss of MoRF binding (P = 0.0164);Loss of MoRF binding (P = 0.0164);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -42
Find out detailed SpliceAI scores and Pangolin per-transcript scores at