rs41265123

chr2-232484141-C-Gchr2-232484141-C-T

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: 7.85

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 128950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232484141-C-G is described in Lovd as [Likely_benign]. Variant chr2-232484141-C-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECEL1	NM_004826.4	c.1267G>C	p.Glu423Gln	missense_variant	7/18	ENST00000304546.6
ECEL1	NM_001290787.2	c.1267G>C	p.Glu423Gln	missense_variant	7/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6	c.1267G>C	p.Glu423Gln	missense_variant	7/18	1	NM_004826.4	P4
ECEL1	ENST00000409941.1	c.1267G>C	p.Glu423Gln	missense_variant	6/17	1		A1
ECEL1	ENST00000482346.1	n.1578G>C		non_coding_transcript_exon_variant	6/17	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

GnomAD3 exomes AF: 0.0144 AC: 3612 AN: 250760 Hom.: 30 AF XY: 0.0150 AC XY: 2032 AN XY: 135634

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 SAS exome AF: 0.00696

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

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.00780

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00741

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0206

Gnomad4 OTH exome AF: 0.0132

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

Gnomad4 AFR AF: 0.00373

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0145

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0137

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 22, 2016	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2021	- -

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs41265123; hg19: chr2-233348851;