rs61731716

Positions:

• chr2-232481151-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004826.4(ECEL1):​c.1995C>T​(p.Asn665Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,564,584 control chromosomes in the GnomAD database, including 443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (39 hom., cov: 34)
  • Exomes 𝑓: 0.022 (404 hom.)
• Consequence: ECEL1 NM_004826.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.65

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-232481151-G-A is Benign according to our data. Variant chr2-232481151-G-A is described in ClinVar as [Benign]. Clinvar id is 128953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0157 (2385/152346) while in subpopulation NFE AF= 0.0238 (1617/68026). AF 95% confidence interval is 0.0228. There are 39 homozygotes in gnomad4. There are 1115 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.1995C>T	p.Asn665Asn	synonymous_variant	15/18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.1989C>T	p.Asn663Asn	synonymous_variant	15/18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.1995C>T	p.Asn665Asn	synonymous_variant	15/18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.1989C>T	p.Asn663Asn	synonymous_variant	14/17	1		ENSP00000386333.1
ECEL1	ENST00000411860.5	c.235-338C>T		intron_variant		3		ENSP00000412683.1
ECEL1	ENST00000482346.1	n.2306C>T		non_coding_transcript_exon_variant	14/17	2

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2386 AN: 152228 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0154 AC: 2669 AN: 172986 Hom.: 38 AF XY: 0.0152 AC XY: 1396 AN XY: 91950

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.00637

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00876

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0218 AC: 30786 AN: 1412238 Hom.: 404 Cov.: 33 AF XY: 0.0214 AC XY: 14917 AN XY: 697888

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.00650

Gnomad4 ASJ exome AF: 0.0262

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.00954

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.0244

Gnomad4 OTH exome AF: 0.0225

GnomAD4 genome AF: 0.0157 AC: 2385 AN: 152346 Hom.: 39 Cov.: 34 AF XY: 0.0150 AC XY: 1115 AN XY: 74494

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00869

Gnomad4 FIN AF: 0.0267

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.0208 Hom.: 56

Bravo AF: 0.0132

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.89

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: rs61731716; hg19: chr2-233345861; COSMIC: COSV58814542;