rs759229479

Variant names:

• chr1-21225424-C-T
• rs759229479
• NM_001397.3:c.1866G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001397.3(ECE1):​c.1866G>A​(p.Lys622Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ECE1 NM_001397.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.968
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-21225424-C-T is Benign according to our data. Variant chr1-21225424-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 763965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.968 with no splicing effect.

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.1866G>A	p.Lys622Lys	synonymous	Exon 17 of 19	NP_001388.1	P42892-1
	ECE1	NM_001113349.2		c.1857G>A	p.Lys619Lys	synonymous	Exon 16 of 18	NP_001106820.1	P42892-4
	ECE1	NM_001113347.2		c.1830G>A	p.Lys610Lys	synonymous	Exon 15 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.1866G>A	p.Lys622Lys	synonymous	Exon 17 of 19	ENSP00000364028.6	P42892-1
	ECE1	ENST00000264205.10	TSL:1	c.1857G>A	p.Lys619Lys	synonymous	Exon 16 of 18	ENSP00000264205.6	P42892-4
	ECE1	ENST00000357071.8	TSL:1	c.1830G>A	p.Lys610Lys	synonymous	Exon 15 of 17	ENSP00000349581.4	P42892-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251098 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727206

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

American (AMR) AF: 0.00 AC: 0 AN: 44712

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

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.48
PhyloP100		0.97
Mutation Taster		=100/0	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: rs759229479; hg19: chr1-21551917;