2-232481123-C-A

Position:

• chr2-232481123-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_004826.4(ECEL1):​c.2023G>T​(p.Ala675Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 1,416,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. A675T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-232481123-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.2023G>T	p.Ala675Ser	missense_variant	15/18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.2017G>T	p.Ala673Ser	missense_variant	15/18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.2023G>T	p.Ala675Ser	missense_variant	15/18	1	NM_004826.4	ENSP00000302051	P4
ECEL1	ENST00000409941.1	c.2017G>T	p.Ala673Ser	missense_variant	14/17	1		ENSP00000386333	A1
ECEL1	ENST00000411860.5	c.235-310G>T		intron_variant		3		ENSP00000412683
ECEL1	ENST00000482346.1	n.2334G>T		non_coding_transcript_exon_variant	14/17	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181008 Hom.: 0 AF XY: 0.0000207 AC XY: 2 AN XY: 96568

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 SAS exome AF: 0.0000831

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1416440 Hom.: 0 Cov.: 33 AF XY: 0.00000428 AC XY: 3 AN XY: 700362

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: 0.0000249

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000169 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.94		Gain of disorder (P = 0.0191);.;
MVP		0.93
MPC		0.59
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231471; hg19: chr2-233345833;