3-184276991-G-A

Position:

• chr3-184276991-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001100121.2(ECE2):​c.226G>A​(p.Gly76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ECE2 NM_001100121.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

Genes affected

ECE2 (HGNC:13275): (endothelin converting enzyme 2) Enables metalloendopeptidase activity. Involved in peptide hormone processing. Located in cytoplasmic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

EEF1AKMT4-ECE2 (HGNC:53615): (EEF1AKMT4-ECE2 readthrough) This gene represents naturally occurring readthrough transcription between adjacent genes eukaryotic translation elongation factor 1 alpha lysine methyltransferase 4 (GeneID: 110599564) and endothelin converting enzyme 2 (GeneID:9718). The readthrough transcript representing this gene encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jul 2017]

ECE2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2864374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECE2	NM_001100121.2	c.226G>A	p.Gly76Ser	missense_variant	3/19	ENST00000404464.8	NP_001093591.1
EEF1AKMT4-ECE2	NM_014693.4	c.580G>A	p.Gly194Ser	missense_variant	3/19		NP_055508.3
ECE2	NM_001100120.2	c.364G>A	p.Gly122Ser	missense_variant	3/19		NP_001093590.1
ECE2	NM_001037324.3	c.139G>A	p.Gly47Ser	missense_variant	2/18		NP_001032401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECE2	ENST00000404464.8	c.226G>A	p.Gly76Ser	missense_variant	3/19	1	NM_001100121.2	ENSP00000385846.3
EEF1AKMT4-ECE2	ENST00000402825.7	c.580G>A	p.Gly194Ser	missense_variant	3/19	1		ENSP00000384223.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461802 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727196

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The c.580G>A (p.G194S) alteration is located in exon 3 (coding exon 3) of the ECE2 gene. This alteration results from a G to A substitution at nucleotide position 580, causing the glycine (G) at amino acid position 194 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	.;.;.;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.71	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.13	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.21	T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Vest4		0.37
MutPred		0.60		Loss of helix (P = 0.0017);.;.;.;.;
MVP		0.71
MPC		0.19
ClinPred		0.77	D
GERP RS		4.3
Varity_R		0.045
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs1246132620; hg19: chr3-183994779;