rs765305996

Variant names:

• chr2-232486160-A-G
• rs765305996
• NM_004826.4:c.494T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004826.4(ECEL1):​c.494T>C​(p.Leu165Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000984 in 1,422,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 4.49
• Publications: 2 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 2-232486160-A-G is Pathogenic according to our data. Variant chr2-232486160-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521056.

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.494T>C	p.Leu165Pro	missense	Exon 2 of 18	NP_004817.2	A0A6F7YIA8
	ECEL1	NM_001290787.2		c.494T>C	p.Leu165Pro	missense	Exon 2 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.494T>C	p.Leu165Pro	missense	Exon 2 of 18	ENSP00000302051.1	O95672-1
	ECEL1	ENST00000409941.1	TSL:1	c.494T>C	p.Leu165Pro	missense	Exon 1 of 17	ENSP00000386333.1	O95672-2
	ECEL1	ENST00000862796.1		c.494T>C	p.Leu165Pro	missense	Exon 2 of 18	ENSP00000532855.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000382 AC: 7 AN: 183120 AF XY: 0.0000684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000984 AC: 14 AN: 1422786 Hom.: 0 Cov.: 32 AF XY: 0.0000156 AC XY: 11 AN XY: 705920

African (AFR) AF: 0.00 AC: 0 AN: 31838

American (AMR) AF: 0.00 AC: 0 AN: 39794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25134

East Asian (EAS) AF: 0.00 AC: 0 AN: 38288

South Asian (SAS) AF: 0.000158 AC: 13 AN: 82352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43126

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098018

Other (OTH) AF: 0.00 AC: 0 AN: 58922

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000259 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Distal arthrogryposis type 5D (3)
-	1	-	Arthrogryposis multiplex congenita (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.41	B
Vest4		0.61
MutPred		0.86		Gain of disorder (P = 0.0166)
MVP		0.82
MPC		2.7
ClinPred		0.89	D
GERP RS		3.9
PromoterAI		0.032	Neutral
Varity_R		0.98
gMVP		0.98
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs765305996; hg19: chr2-233350870;