rs1190429

Variant names:

• chr2-232482880-C-T
• rs1190429
• NM_004826.4:c.1656G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004826.4(ECEL1):​c.1656G>A​(p.Lys552Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,614,200 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (32 hom.)
• Consequence: ECEL1 NM_004826.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.29
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-232482880-C-T is Benign according to our data. Variant chr2-232482880-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0044 (671/152404) while in subpopulation NFE AF = 0.00707 (481/68048). AF 95% confidence interval is 0.00655. There are 1 homozygotes in GnomAd4. There are 301 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 32 AR gene

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.1656G>A	p.Lys552Lys	synonymous	Exon 10 of 18	NP_004817.2	A0A6F7YIA8
	ECEL1	NM_001290787.2		c.1656G>A	p.Lys552Lys	synonymous	Exon 10 of 18	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.1656G>A	p.Lys552Lys	synonymous	Exon 10 of 18	ENSP00000302051.1	O95672-1
	ECEL1	ENST00000409941.1	TSL:1	c.1656G>A	p.Lys552Lys	synonymous	Exon 9 of 17	ENSP00000386333.1	O95672-2
	ECEL1	ENST00000862796.1		c.1656G>A	p.Lys552Lys	synonymous	Exon 10 of 18	ENSP00000532855.1

Frequencies

GnomAD3 genomes AF: 0.00441 AC: 671 AN: 152286 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00357 AC: 898 AN: 251410 AF XY: 0.00372

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00606 AC: 8852 AN: 1461796 Hom.: 32 Cov.: 33 AF XY: 0.00582 AC XY: 4233 AN XY: 727204

African (AFR) AF: 0.00131 AC: 44 AN: 33478

American (AMR) AF: 0.00391 AC: 175 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00169 AC: 90 AN: 53346

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00737 AC: 8193 AN: 1111998

Other (OTH) AF: 0.00555 AC: 335 AN: 60392

GnomAD4 genome AF: 0.00440 AC: 671 AN: 152404 Hom.: 1 Cov.: 33 AF XY: 0.00404 AC XY: 301 AN XY: 74530

African (AFR) AF: 0.00159 AC: 66 AN: 41602

American (AMR) AF: 0.00653 AC: 100 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00103 AC: 11 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00707 AC: 481 AN: 68048

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00522 Hom.: 2

Bravo AF: 0.00490

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	ECEL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		3.3
PromoterAI		-0.048	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1190429; hg19: chr2-233347590;