NM_004826.4:c.1267G>C

Variant names:

• chr2-232484141-C-G
• rs41265123
• NM_004826.4:c.1267G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004826.4(ECEL1):​c.1267G>C​(p.Glu423Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,613,730 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 33)
  • Exomes 𝑓: 0.018 (290 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.85
• Publications: 9 publications found

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]

ECEL1 Gene-Disease associations (from GenCC):

• distal arthrogryposis type 5D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010414183).
• BP6: Variant 2-232484141-C-G is Benign according to our data. Variant chr2-232484141-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2030/152350) while in subpopulation NFE AF = 0.0218 (1485/68030). AF 95% confidence interval is 0.0209. There are 21 homozygotes in GnomAd4. There are 994 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.1267G>C	p.Glu423Gln	missense_variant	Exon 7 of 18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.1267G>C	p.Glu423Gln	missense_variant	Exon 7 of 18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.1267G>C	p.Glu423Gln	missense_variant	Exon 7 of 18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.1267G>C	p.Glu423Gln	missense_variant	Exon 6 of 17	1		ENSP00000386333.1
ECEL1	ENST00000482346.1	n.1578G>C		non_coding_transcript_exon_variant	Exon 6 of 17	2

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2031 AN: 152232 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.0144 AC: 3612 AN: 250760 AF XY: 0.0150

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0176 AC: 25710 AN: 1461380 Hom.: 290 Cov.: 33 AF XY: 0.0176 AC XY: 12826 AN XY: 727004

African (AFR) AF: 0.00284 AC: 95 AN: 33480

American (AMR) AF: 0.00780 AC: 349 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 21 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00741 AC: 639 AN: 86252

European-Finnish (FIN) AF: 0.0145 AC: 768 AN: 52948

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5760

European-Non Finnish (NFE) AF: 0.0206 AC: 22935 AN: 1111992

Other (OTH) AF: 0.0132 AC: 796 AN: 60390

GnomAD4 genome AF: 0.0133 AC: 2030 AN: 152350 Hom.: 21 Cov.: 33 AF XY: 0.0133 AC XY: 994 AN XY: 74494

African (AFR) AF: 0.00373 AC: 155 AN: 41580

American (AMR) AF: 0.0116 AC: 178 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1485 AN: 68030

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0111 Hom.: 5

Bravo AF: 0.0128

TwinsUK AF: 0.0224 AC: 83

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0144 AC: 1750

EpiCase AF: 0.0248

EpiControl AF: 0.0252

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ECEL1: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Apr 22, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	0.023
Eigen_PC	Benign	0.054
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		7.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.15	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.72	P;P
Vest4		0.22
MPC		0.51
ClinPred		0.030	T
GERP RS		4.5
Varity_R		0.33
gMVP		0.35
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs41265123; hg19: chr2-233348851; COSMIC: COSV108095814; COSMIC: COSV108095814;