chr2-232484156-G-T

Position:

• chr2-232484156-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000304546.6(ECEL1):​c.1252C>A​(p.Arg418Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R418C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ECEL1 ENST00000304546.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.75

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a disulfide_bond (size 254) in uniprot entity ECEL1_HUMAN there are 21 pathogenic changes around while only 9 benign (70%) in ENST00000304546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-232484156-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 2-232484156-G-T is Pathogenic according to our data. Variant chr2-232484156-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 39490.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-232484156-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.1252C>A	p.Arg418Ser	missense_variant	7/18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.1252C>A	p.Arg418Ser	missense_variant	7/18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.1252C>A	p.Arg418Ser	missense_variant	7/18	1	NM_004826.4	ENSP00000302051	P4
ECEL1	ENST00000409941.1	c.1252C>A	p.Arg418Ser	missense_variant	6/17	1		ENSP00000386333	A1
ECEL1	ENST00000482346.1	n.1563C>A		non_coding_transcript_exon_variant	6/17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Distal arthrogryposis type 5D Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 10, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.039	D;D
Polyphen		0.99	D;P
Vest4		0.93
MVP		0.90
MPC		0.65
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776919; hg19: chr2-233348866;