rs5349
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_001122659.3(EDNRB):c.561C>T(p.Ile187=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00468 in 1,612,902 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.011 ( 23 hom., cov: 32)
Exomes 𝑓: 0.0040 ( 41 hom. )
Consequence
EDNRB
NM_001122659.3 synonymous
NM_001122659.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.84
Genes affected
EDNRB (HGNC:3180): (endothelin receptor type B) The protein encoded by this gene is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three potent vasoactive peptides: ET1, ET2, and ET3. Studies suggest that the multigenic disorder, Hirschsprung disease type 2, is due to mutations in the endothelin receptor type B gene. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -18 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.29).
BP6
Variant 13-77903530-G-A is Benign according to our data. Variant chr13-77903530-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1643/152036) while in subpopulation AFR AF= 0.0282 (1171/41518). AF 95% confidence interval is 0.0269. There are 23 homozygotes in gnomad4. There are 766 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 23 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EDNRB | NM_001122659.3 | c.561C>T | p.Ile187= | synonymous_variant | 2/7 | ENST00000646607.2 | NP_001116131.1 | |
EDNRB-AS1 | NR_103853.1 | n.1695-4162G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EDNRB | ENST00000646607.2 | c.561C>T | p.Ile187= | synonymous_variant | 2/7 | NM_001122659.3 | ENSP00000493527 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0108 AC: 1635AN: 151918Hom.: 22 Cov.: 32
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GnomAD3 exomes AF: 0.00548 AC: 1373AN: 250324Hom.: 9 AF XY: 0.00502 AC XY: 679AN XY: 135290
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GnomAD4 exome AF: 0.00404 AC: 5903AN: 1460866Hom.: 41 Cov.: 31 AF XY: 0.00389 AC XY: 2830AN XY: 726764
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GnomAD4 genome AF: 0.0108 AC: 1643AN: 152036Hom.: 23 Cov.: 32 AF XY: 0.0103 AC XY: 766AN XY: 74306
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 13, 2015 | p.Ile277Ile in exon 3 of EDNRB: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 2.9% (128/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs5349). - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 09, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 03, 2021 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2018 | This variant is associated with the following publications: (PMID: 17618893, 12628594, 22993632, 20009762) - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Hirschsprung disease, susceptibility to, 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at