chr2-232480202-C-A

Variant names:

• chr2-232480202-C-A
• rs2106181415
• NM_004826.4:c.2279G>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.2279G>T​(p.Cys760Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C760R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

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 chr2-232480203-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 100650.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004826.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	NM_004826.4	MANE Select	c.2279G>T	p.Cys760Phe	missense	Exon 18 of 18	NP_004817.2	A0A6F7YIA8
	ECEL1	NM_001290787.2		c.2273G>T	p.Cys758Phe	missense	Exon 18 of 18	NP_001277716.1	O95672-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	ENST00000304546.6	TSL:1 MANE Select	c.2279G>T	p.Cys760Phe	missense	Exon 18 of 18	ENSP00000302051.1	O95672-1
	ECEL1	ENST00000409941.1	TSL:1	c.2273G>T	p.Cys758Phe	missense	Exon 17 of 17	ENSP00000386333.1	O95672-2
	ECEL1	ENST00000862796.1		c.2279G>T	p.Cys760Phe	missense	Exon 18 of 18	ENSP00000532855.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Distal arthrogryposis type 5D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.90		Loss of catalytic residue at C760 (P = 0.1085)
MVP		0.94
MPC		0.77
ClinPred		1.0	D
GERP RS		5.2
Varity_R		1.0
gMVP		0.91
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2106181415; hg19: chr2-233344912; COSMIC: COSV58813532;