rs76735188

Positions:

• chr2-232484900-G-C

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.967-7C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,613,230 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (12 hom., cov: 34)
  • Exomes 𝑓: 0.013 (143 hom.)
• Consequence: ECEL1 NM_004826.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01538
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0240

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 (BayesDel_noAF=-0.82).
• BP6: Variant 2-232484900-G-C is Benign according to our data. Variant chr2-232484900-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 128956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232484900-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0088 (1341/152318) while in subpopulation NFE AF= 0.0142 (964/68016). AF 95% confidence interval is 0.0134. There are 12 homozygotes in gnomad4. There are 643 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.967-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.967-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.967-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004826.4	ENSP00000302051	P4
ECEL1	ENST00000409941.1	c.967-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000386333	A1
ECEL1	ENST00000482346.1	n.1278-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1340 AN: 152200 Hom.: 12 Cov.: 34

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00876 AC: 2196 AN: 250802 Hom.: 17 AF XY: 0.00865 AC XY: 1173 AN XY: 135590

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0128 AC: 18701 AN: 1460912 Hom.: 143 Cov.: 60 AF XY: 0.0124 AC XY: 9006 AN XY: 726782

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00232

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.00880 AC: 1341 AN: 152318 Hom.: 12 Cov.: 34 AF XY: 0.00863 AC XY: 643 AN XY: 74480

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0147

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.0105 Hom.: 3

Bravo AF: 0.00829

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2021	- -
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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ECEL1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.1
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.12
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: rs76735188; hg19: chr2-233349610;