chr1-21227944-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3	c.1768C>G	p.Arg590Gly	missense_variant	Exon 15 of 19	ENST00000374893.11	NP_001388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11	c.1768C>G	p.Arg590Gly	missense_variant	Exon 15 of 19	1	NM_001397.3	ENSP00000364028.6

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

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: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	0.039
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Benign	1.2	.;.;.;L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N;.;N;N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.38	T;.;T;T;T;T
Sift4G	Benign	0.45	T;.;T;T;T;T
Polyphen		0.38, 0.0060, 0.023	.;.;B;B;B;B
Vest4		0.57
MutPred		0.53		.;.;.;Gain of ubiquitination at K594 (P = 0.0581);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-21554437;