2-232480215-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004826.4(ECEL1):c.2266C>T(p.Arg756Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.47

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECEL1	NM_004826.4	c.2266C>T	p.Arg756Trp	missense_variant	18/18	ENST00000304546.6
ECEL1	NM_001290787.2	c.2260C>T	p.Arg754Trp	missense_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6	c.2266C>T	p.Arg756Trp	missense_variant	18/18	1	NM_004826.4	P4
ECEL1	ENST00000409941.1	c.2260C>T	p.Arg754Trp	missense_variant	17/17	1		A1
ECEL1	ENST00000411860.5	c.445C>T	p.Arg149Trp	missense_variant	6/6	3
ECEL1	ENST00000482346.1	n.2577C>T		non_coding_transcript_exon_variant	17/17	2

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000247 AC: 62 AN: 251026 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135712

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000416 AC: 608 AN: 1461786 Hom.: 0 Cov.: 32 AF XY: 0.000397 AC XY: 289 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000517

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74440

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000709

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The c.2266C>T (p.R756W) alteration is located in exon 18 (coding exon 17) of the ECEL1 gene. This alteration results from a C to T substitution at nucleotide position 2266, causing the arginine (R) at amino acid position 756 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.72, 0.69
MVP		0.86
MPC		0.63
ClinPred		0.68	D
GERP RS		5.2
Varity_R		0.78
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs147861587; hg19: chr2-233344925; COSMIC: COSV58813717;