chr2-232480456-C-A

Variant names:

• chr2-232480456-C-A
• rs150438393
• NM_004826.4:c.2171G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004826.4(ECEL1):​c.2171G>T​(p.Arg724Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.2171G>T	p.Arg724Leu	missense_variant	Exon 17 of 18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.2165G>T	p.Arg722Leu	missense_variant	Exon 17 of 18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.2171G>T	p.Arg724Leu	missense_variant	Exon 17 of 18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.2165G>T	p.Arg722Leu	missense_variant	Exon 16 of 17	1		ENSP00000386333.1
ECEL1	ENST00000411860.5	c.350G>T	p.Arg117Leu	missense_variant	Exon 5 of 6	3		ENSP00000412683.1
ECEL1	ENST00000482346.1	n.2482G>T		non_coding_transcript_exon_variant	Exon 16 of 17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251162 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461610 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.098	T;T;T
Polyphen		0.99, 0.013	.;D;B
Vest4		0.92, 0.92
MutPred		0.81		.;Loss of MoRF binding (P = 0.049);.;
MVP		0.85
MPC		0.69
ClinPred		0.43	T
GERP RS		5.4
Varity_R		0.61
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs150438393; hg19: chr2-233345166;