2-232480239-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.43

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 4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.2242G>A	p.Val748Met	missense_variant	Exon 18 of 18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.2236G>A	p.Val746Met	missense_variant	Exon 18 of 18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.2242G>A	p.Val748Met	missense_variant	Exon 18 of 18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.2236G>A	p.Val746Met	missense_variant	Exon 17 of 17	1		ENSP00000386333.1
ECEL1	ENST00000411860.5	c.421G>A	p.Val141Met	missense_variant	Exon 6 of 6	3		ENSP00000412683.1
ECEL1	ENST00000482346.1	n.2553G>A		non_coding_transcript_exon_variant	Exon 17 of 17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	0.57	.;N;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.62	N;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.041	D;D;D
Sift4G	Uncertain	0.049	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.68, 0.83
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1027424558; hg19: chr2-233344949;