chr3-184277376-C-T

Variant names:

• chr3-184277376-C-T
• rs138696988
• NM_001100121.2:c.388C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001100121.2(ECE2):​c.388C>T​(p.Arg130Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R130Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: ECE2 NM_001100121.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• Publications: 1 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793
• BS2: High AC in GnomAd4 at 11 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.388C>T	p.Arg130Trp	missense	Exon 4 of 19	NP_001093591.1	P0DPD6-2
	EEF1AKMT4-ECE2	NM_014693.4		c.742C>T	p.Arg248Trp	missense	Exon 4 of 19	NP_055508.3
	ECE2	NM_001100120.2		c.526C>T	p.Arg176Trp	missense	Exon 4 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.388C>T	p.Arg130Trp	missense	Exon 4 of 19	ENSP00000385846.3	P0DPD6-2
	EEF1AKMT4-ECE2	ENST00000402825.7	TSL:1	c.742C>T	p.Arg248Trp	missense	Exon 4 of 19	ENSP00000384223.3	P0DPD8-1
	ECE2	ENST00000357474.9	TSL:1	c.526C>T	p.Arg176Trp	missense	Exon 4 of 19	ENSP00000350066.5	P0DPD6-4

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251452 AF XY: 0.0000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000896 AC: 131 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.0000949 AC XY: 69 AN XY: 727244

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000114 AC: 127 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.000262 AC: 4 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.16
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.20	D
PhyloP100		2.2
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.43
MVP		0.85
MPC		0.65
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.13
gMVP		0.69
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs138696988; hg19: chr3-183995164; COSMIC: COSV105909671; COSMIC: COSV105909671;