chr2-232480161-C-T

Variant names:

• chr2-232480161-C-T
• rs149447864
• NM_004826.4:c.2320G>A

Variant summary

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

The NM_004826.4(ECEL1):​c.2320G>A​(p.Val774Met) variant causes a missense change. The variant allele was found at a frequency of 0.000132 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.64

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 rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.2320G>A	p.Val774Met	missense_variant	Exon 18 of 18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.2314G>A	p.Val772Met	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.2320G>A	p.Val774Met	missense_variant	Exon 18 of 18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.2314G>A	p.Val772Met	missense_variant	Exon 17 of 17	1		ENSP00000386333.1
ECEL1	ENST00000411860.5	c.499G>A	p.Val167Met	missense_variant	Exon 6 of 6	3		ENSP00000412683.1
ECEL1	ENST00000482346.1	n.2631G>A		non_coding_transcript_exon_variant	Exon 17 of 17	2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151822 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 250418 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135382

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1461590 Hom.: 0 Cov.: 32 AF XY: 0.000140 AC XY: 102 AN XY: 727108

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151940 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74288

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2320G>A (p.V774M) alteration is located in exon 18 (coding exon 17) of the ECEL1 gene. This alteration results from a G to A substitution at nucleotide position 2320, causing the valine (V) at amino acid position 774 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Distal arthrogryposis type 5D Uncertain:1

Jul 16, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

May 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.12	T;D;D
Polyphen		1.0, 0.99	.;D;D
Vest4		0.75, 0.83
MVP		0.90
MPC		0.59
ClinPred		0.46	T
GERP RS		5.1
Varity_R		0.73
gMVP		0.69

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: rs149447864; hg19: chr2-233344871;