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. The variant received -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
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• distal arthrogryposis type 5D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004826.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	NM_004826.4	MANE Select	c.2229-29A>C		intron	N/A	NP_004817.2	A0A6F7YIA8
	ECEL1	NM_001290787.2		c.2223-29A>C		intron	N/A	NP_001277716.1	O95672-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	ENST00000304546.6	TSL:1 MANE Select	c.2229-29A>C		intron	N/A	ENSP00000302051.1	O95672-1
	ECEL1	ENST00000409941.1	TSL:1	c.2223-29A>C		intron	N/A	ENSP00000386333.1	O95672-2
	ECEL1	ENST00000862796.1		c.2229-29A>C		intron	N/A	ENSP00000532855.1

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

GnomAD2 exomes AF: 0.515 AC: 127300 AN: 247124 AF XY: 0.510

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 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

African (AFR) AF: 0.521 AC: 17439 AN: 33452

American (AMR) AF: 0.596 AC: 26559 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 11665 AN: 26096

East Asian (EAS) AF: 0.678 AC: 26873 AN: 39660

South Asian (SAS) AF: 0.517 AC: 44593 AN: 86184

European-Finnish (FIN) AF: 0.518 AC: 27469 AN: 53022

Middle Eastern (MID) AF: 0.482 AC: 2777 AN: 5762

European-Non Finnish (NFE) AF: 0.458 AC: 509221 AN: 1110928

Other (OTH) AF: 0.481 AC: 29023 AN: 60284

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

African (AFR) AF: 0.521 AC: 21589 AN: 41412

American (AMR) AF: 0.570 AC: 8708 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1495 AN: 3464

East Asian (EAS) AF: 0.686 AC: 3520 AN: 5132

South Asian (SAS) AF: 0.508 AC: 2446 AN: 4812

European-Finnish (FIN) AF: 0.516 AC: 5449 AN: 10556

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30933 AN: 67886

Other (OTH) AF: 0.476 AC: 1001 AN: 2104

Alfa AF: 0.474 Hom.: 3150

Bravo AF: 0.503

Asia WGS AF: 0.585 AC: 2033 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Distal arthrogryposis type 5D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.73
PhyloP100		0.52
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2741279; hg19: chr2-233344991;