1-21227944-G-C

Variant names:

• chr1-21227944-G-C
• rs147818649
• NM_001397.3:c.1768C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001397.3(ECE1):​c.1768C>G​(p.Arg590Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000713 in 1,402,246 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. R590C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ECE1 NM_001397.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.00
• Publications: 0 publications found

Genes affected

ECE1 (HGNC:3146): (endothelin converting enzyme 1) The protein encoded by this gene is involved in proteolytic processing of endothelin precursors to biologically active peptides. Mutations in this gene are associated with Hirschsprung disease, cardiac defects and autonomic dysfunction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Sep 2009]

ECE1 Gene-Disease associations (from GenCC):

• essential hypertension, genetic

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001397.3. 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
	ECE1	NM_001397.3	MANE Select	c.1768C>G	p.Arg590Gly	missense	Exon 15 of 19	NP_001388.1	P42892-1
	ECE1	NM_001113349.2		c.1759C>G	p.Arg587Gly	missense	Exon 14 of 18	NP_001106820.1	P42892-4
	ECE1	NM_001113347.2		c.1732C>G	p.Arg578Gly	missense	Exon 13 of 17	NP_001106818.1	P42892-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECE1	ENST00000374893.11	TSL:1 MANE Select	c.1768C>G	p.Arg590Gly	missense	Exon 15 of 19	ENSP00000364028.6	P42892-1
	ECE1	ENST00000264205.10	TSL:1	c.1759C>G	p.Arg587Gly	missense	Exon 14 of 18	ENSP00000264205.6	P42892-4
	ECE1	ENST00000357071.8	TSL:1	c.1732C>G	p.Arg578Gly	missense	Exon 13 of 17	ENSP00000349581.4	P42892-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402246 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691850

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31822

American (AMR) AF: 0.00 AC: 0 AN: 36260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.00 AC: 0 AN: 36100

South Asian (SAS) AF: 0.00 AC: 0 AN: 79480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080096

Other (OTH) AF: 0.0000172 AC: 1 AN: 58104

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.039
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.64
Sift	Benign	0.38	T
Sift4G	Benign	0.45	T
Polyphen		0.38	B
Vest4		0.57
MutPred		0.53		Gain of ubiquitination at K594 (P = 0.0581)
MVP		0.95
MPC		1.3
ClinPred		0.88	D
GERP RS		3.8
Varity_R		0.31
gMVP		0.66
Mutation Taster		=36/64	disease causing

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: rs147818649; hg19: chr1-21554437;