2-232484878-G-C

Position:

• chr2-232484878-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004826.4(ECEL1):​c.982C>G​(p.His328Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. H328Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a disulfide_bond (size 254) in uniprot entity ECEL1_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_004826.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15902022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.982C>G	p.His328Asp	missense_variant	5/18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.982C>G	p.His328Asp	missense_variant	5/18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.982C>G	p.His328Asp	missense_variant	5/18	1	NM_004826.4	ENSP00000302051	P4
ECEL1	ENST00000409941.1	c.982C>G	p.His328Asp	missense_variant	4/17	1		ENSP00000386333	A1
ECEL1	ENST00000482346.1	n.1293C>G		non_coding_transcript_exon_variant	4/17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.48	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.23
Sift	Benign	0.16	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0	B;B
Vest4		0.21
MutPred		0.42		Gain of disorder (P = 0.0681);Gain of disorder (P = 0.0681);
MVP		0.63
MPC		0.19
ClinPred		0.54	D
GERP RS		4.9
Varity_R		0.092
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1529874; hg19: chr2-233349588;