3-184276991-G-A

Variant names:

• chr3-184276991-G-A
• rs1246132620
• NM_001100121.2:c.226G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

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. 15/21 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
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2864374).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100121.2. 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
	ECE2	NM_001100121.2	MANE Select	c.226G>A	p.Gly76Ser	missense	Exon 3 of 19	NP_001093591.1	P0DPD6-2
	EEF1AKMT4-ECE2	NM_014693.4		c.580G>A	p.Gly194Ser	missense	Exon 3 of 19	NP_055508.3
	ECE2	NM_001100120.2		c.364G>A	p.Gly122Ser	missense	Exon 3 of 19	NP_001093590.1	P0DPD6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECE2	ENST00000404464.8	TSL:1 MANE Select	c.226G>A	p.Gly76Ser	missense	Exon 3 of 19	ENSP00000385846.3	P0DPD6-2
	EEF1AKMT4-ECE2	ENST00000402825.7	TSL:1	c.580G>A	p.Gly194Ser	missense	Exon 3 of 19	ENSP00000384223.3	P0DPD8-1
	ECE2	ENST00000357474.9	TSL:1	c.364G>A	p.Gly122Ser	missense	Exon 3 of 19	ENSP00000350066.5	P0DPD6-4

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111988

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.71	T
PhyloP100		3.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.15
Sift	Benign	0.21	T
Sift4G	Benign	0.47	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
PromoterAI		-0.0058	Neutral
Varity_R		0.045
gMVP		0.63
Mutation Taster		=80/20	polymorphism

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: rs1246132620; hg19: chr3-183994779;