chr2-232480239-C-T

Variant names:

• chr2-232480239-C-T
• rs1027424558
• NM_004826.4:c.2242G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004826.4(ECEL1):​c.2242G>A​(p.Val748Met) 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. 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. V748L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

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.2242G>A	p.Val748Met	missense	Exon 18 of 18	NP_004817.2	A0A6F7YIA8
	ECEL1	NM_001290787.2		c.2236G>A	p.Val746Met	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.2242G>A	p.Val748Met	missense	Exon 18 of 18	ENSP00000302051.1	O95672-1
	ECEL1	ENST00000409941.1	TSL:1	c.2236G>A	p.Val746Met	missense	Exon 17 of 17	ENSP00000386333.1	O95672-2
	ECEL1	ENST00000862796.1		c.2242G>A	p.Val748Met	missense	Exon 18 of 18	ENSP00000532855.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	0.57	N
PhyloP100		7.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.62	N
REVEL	Pathogenic	0.70
Sift	Benign	0.041	D
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.83		Gain of catalytic residue at V744 (P = 0.0191)
MVP		0.84
MPC		0.61
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.42
gMVP		0.55
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs1027424558; hg19: chr2-233344949;