2-232484472-C-A

Variant names:

• chr2-232484472-C-A
• rs765430577
• NM_004826.4:c.1184G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_004826.4(ECEL1):​c.1184G>T​(p.Arg395Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R395Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.68
• Publications: 5 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.1184G>T	p.Arg395Leu	missense_variant, splice_region_variant	Exon 6 of 18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.1184G>T	p.Arg395Leu	missense_variant, splice_region_variant	Exon 6 of 18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.1184G>T	p.Arg395Leu	missense_variant, splice_region_variant	Exon 6 of 18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.1184G>T	p.Arg395Leu	missense_variant, splice_region_variant	Exon 5 of 17	1		ENSP00000386333.1
ECEL1	ENST00000482346.1	n.1495G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461240 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726880

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111742

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	35
DANN	Benign	0.97
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		3.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.57
Sift	Benign	0.12	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.80	P;P
Vest4		0.79
MutPred		0.54		Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);
MVP		0.84
MPC		0.47
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.62
gMVP		0.75
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: -42
DS_DL_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765430577; hg19: chr2-233349182;