2-232480086-T-A

Position:

• chr2-232480086-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004826.4(ECEL1):​c.*67A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,510,460 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (15 hom.)
• Consequence: ECEL1 NM_004826.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.449

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-232480086-T-A is Benign according to our data. Variant chr2-232480086-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1208946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1610/152196) while in subpopulation AFR AF= 0.0366 (1521/41546). AF 95% confidence interval is 0.0351. There are 37 homozygotes in gnomad4. There are 750 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECEL1	NM_004826.4	c.*67A>T		3_prime_UTR_variant	18/18	ENST00000304546.6
ECEL1	NM_001290787.2	c.*67A>T		3_prime_UTR_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6	c.*67A>T		3_prime_UTR_variant	18/18	1	NM_004826.4	P4
ECEL1	ENST00000411860.5	c.*67A>T		3_prime_UTR_variant	6/6	3
ECEL1	ENST00000482346.1	n.2706A>T		non_coding_transcript_exon_variant	17/17	2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1608 AN: 152074 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.00130 AC: 1760 AN: 1358264 Hom.: 15 Cov.: 24 AF XY: 0.00116 AC XY: 784 AN XY: 678092

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.000977

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000225

Gnomad4 OTH exome AF: 0.00249

GnomAD4 genome AF: 0.0106 AC: 1610 AN: 152196 Hom.: 37 Cov.: 33 AF XY: 0.0101 AC XY: 750 AN XY: 74406

Gnomad4 AFR AF: 0.0366

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00807 Hom.: 0

Bravo AF: 0.0122

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.87

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: rs114966878; hg19: chr2-233344796;