rs6750085

Variant names:

• chr2-232483209-C-G
• rs6750085
• NM_004826.4:c.1507-30G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004826.4(ECEL1):​c.1507-30G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,583,368 control chromosomes in the GnomAD database, including 134,034 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10580 hom., cov: 33)
  • Exomes 𝑓: 0.41 (123454 hom.)
• Consequence: ECEL1 NM_004826.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.391
• Publications: 7 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 (BayesDel_noAF=-0.84).
• BP6: Variant 2-232483209-C-G is Benign according to our data. Variant chr2-232483209-C-G is described in ClinVar as Benign. ClinVar VariationId is 1250015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.1507-30G>C		intron_variant	Intron 8 of 17	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.1507-30G>C		intron_variant	Intron 8 of 17		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.1507-30G>C		intron_variant	Intron 8 of 17	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.1507-30G>C		intron_variant	Intron 7 of 16	1		ENSP00000386333.1
ECEL1	ENST00000482346.1	n.1818-30G>C		intron_variant	Intron 7 of 16	2

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54671 AN: 151958 Hom.: 10584 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.405

GnomAD2 exomes AF: 0.393 AC: 78109 AN: 199000 AF XY: 0.397

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.269

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.412 AC: 589493 AN: 1431296 Hom.: 123454 Cov.: 40 AF XY: 0.411 AC XY: 291447 AN XY: 709178

African (AFR) AF: 0.210 AC: 6932 AN: 33086

American (AMR) AF: 0.354 AC: 13673 AN: 38616

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 12191 AN: 25580

East Asian (EAS) AF: 0.279 AC: 10716 AN: 38466

South Asian (SAS) AF: 0.344 AC: 28484 AN: 82746

European-Finnish (FIN) AF: 0.418 AC: 21131 AN: 50580

Middle Eastern (MID) AF: 0.428 AC: 2450 AN: 5730

European-Non Finnish (NFE) AF: 0.429 AC: 470199 AN: 1097198

Other (OTH) AF: 0.400 AC: 23717 AN: 59294

GnomAD4 genome AF: 0.359 AC: 54663 AN: 152072 Hom.: 10580 Cov.: 33 AF XY: 0.360 AC XY: 26777 AN XY: 74318

African (AFR) AF: 0.216 AC: 8968 AN: 41520

American (AMR) AF: 0.359 AC: 5485 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1712 AN: 3472

East Asian (EAS) AF: 0.262 AC: 1345 AN: 5142

South Asian (SAS) AF: 0.346 AC: 1671 AN: 4824

European-Finnish (FIN) AF: 0.428 AC: 4522 AN: 10572

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29480 AN: 67946

Other (OTH) AF: 0.402 AC: 848 AN: 2108

Alfa AF: 0.406 Hom.: 2384

Bravo AF: 0.350

Asia WGS AF: 0.307 AC: 1068 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Distal arthrogryposis type 5D Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.1
DANN	Benign	0.59
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6750085; hg19: chr2-233347919; COSMIC: COSV58811117; COSMIC: COSV58811117;