NM_004826.4:c.590G>C

Variant names:

• chr2-232486064-C-G
• NM_004826.4:c.590G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_004826.4(ECEL1):​c.590G>C​(p.Gly197Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,422 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G197D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.85

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 254) in uniprot entity ECEL1_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_004826.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-232486064-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.590G>C	p.Gly197Ala	missense_variant	Exon 2 of 18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.590G>C	p.Gly197Ala	missense_variant	Exon 2 of 18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.590G>C	p.Gly197Ala	missense_variant	Exon 2 of 18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.590G>C	p.Gly197Ala	missense_variant	Exon 1 of 17	1		ENSP00000386333.1
ECEL1	ENST00000482346.1	n.794G>C		non_coding_transcript_exon_variant	Exon 2 of 17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453422 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722642

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.015	B;D
Vest4		0.27
MutPred		0.73		Loss of disorder (P = 0.125);Loss of disorder (P = 0.125);
MVP		0.85
MPC		0.61
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.55
gMVP		0.90

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233350774;