chr2-232481859-C-T

Position:

• chr2-232481859-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.1797-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,613,722 control chromosomes in the GnomAD database, including 802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (63 hom., cov: 34)
  • Exomes 𝑓: 0.029 (739 hom.)
• Consequence: ECEL1 NM_004826.4 intron
• Scores: Splicing: ADA: 0.00001602
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.68

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-232481859-C-T is Benign according to our data. Variant chr2-232481859-C-T is described in ClinVar as [Benign]. Clinvar id is 128951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232481859-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0244 (3717/152348) while in subpopulation NFE AF= 0.0337 (2295/68022). AF 95% confidence interval is 0.0326. There are 63 homozygotes in gnomad4. There are 1833 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.1797-10G>A		intron_variant		ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.1791-10G>A		intron_variant			NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.1797-10G>A		intron_variant		1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.1791-10G>A		intron_variant		1		ENSP00000386333.1
ECEL1	ENST00000411860.5	c.42-10G>A		intron_variant		3		ENSP00000412683.1
ECEL1	ENST00000482346.1	n.2108-10G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3716 AN: 152230 Hom.: 63 Cov.: 34

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.0534

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0251 AC: 6301 AN: 250762 Hom.: 115 AF XY: 0.0253 AC XY: 3431 AN XY: 135714

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00366

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.0342

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0289 AC: 42184 AN: 1461374 Hom.: 739 Cov.: 38 AF XY: 0.0283 AC XY: 20553 AN XY: 726980

Gnomad4 AFR exome AF: 0.00505

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00458

Gnomad4 FIN exome AF: 0.0516

Gnomad4 NFE exome AF: 0.0320

Gnomad4 OTH exome AF: 0.0271

GnomAD4 genome AF: 0.0244 AC: 3717 AN: 152348 Hom.: 63 Cov.: 34 AF XY: 0.0246 AC XY: 1833 AN XY: 74504

Gnomad4 AFR AF: 0.00560

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.0534

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0198 Hom.: 14

Bravo AF: 0.0226

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 20, 2016	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0090
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs76290356; hg19: chr2-233346569;