NM_004826.4:c.2229-29A>C

Variant names:

• chr2-232480281-T-G
• rs2741279
• NM_004826.4:c.2229-29A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004826.4(ECEL1):​c.2229-29A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,611,826 control chromosomes in the GnomAD database, including 186,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.50 (19080 hom., cov: 32)
  • Exomes 𝑓: 0.48 (167710 hom.)
• Consequence: ECEL1 NM_004826.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.522

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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-232480281-T-G is Benign according to our data. Variant chr2-232480281-T-G is described in ClinVar as [Benign]. Clinvar id is 1255365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.2229-29A>C		intron_variant	Intron 17 of 17	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.2223-29A>C		intron_variant	Intron 17 of 17		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.2229-29A>C		intron_variant	Intron 17 of 17	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.2223-29A>C		intron_variant	Intron 16 of 16	1		ENSP00000386333.1
ECEL1	ENST00000411860.5	c.408-29A>C		intron_variant	Intron 5 of 5	3		ENSP00000412683.1
ECEL1	ENST00000482346.1	n.2540-29A>C		intron_variant	Intron 16 of 16	2

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75511 AN: 151722 Hom.: 19064 Cov.: 32

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.475

GnomAD3 exomes AF: 0.515 AC: 127300 AN: 247124 Hom.: 33299 AF XY: 0.510 AC XY: 68298 AN XY: 133866

Gnomad AFR exome AF: 0.530

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.689

Gnomad SAS exome AF: 0.518

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.464

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.476 AC: 695619 AN: 1459986 Hom.: 167710 Cov.: 36 AF XY: 0.477 AC XY: 346375 AN XY: 726304

Gnomad4 AFR exome AF: 0.521

Gnomad4 AMR exome AF: 0.596

Gnomad4 ASJ exome AF: 0.447

Gnomad4 EAS exome AF: 0.678

Gnomad4 SAS exome AF: 0.517

Gnomad4 FIN exome AF: 0.518

Gnomad4 NFE exome AF: 0.458

Gnomad4 OTH exome AF: 0.481

GnomAD4 genome AF: 0.498 AC: 75577 AN: 151840 Hom.: 19080 Cov.: 32 AF XY: 0.502 AC XY: 37268 AN XY: 74242

Gnomad4 AFR AF: 0.521

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.686

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.516

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.476

Alfa AF: 0.474 Hom.: 3150

Bravo AF: 0.503

Asia WGS AF: 0.585 AC: 2033 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	4.4
DANN	Benign	0.73
BranchPoint Hunter		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2741279; hg19: chr2-233344991;