chr13-77903339-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001122659.3(EDNRB):c.618G>A(p.Trp206Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,986 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
EDNRB
NM_001122659.3 stop_gained
NM_001122659.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.50
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-77903339-C-T is Pathogenic according to our data. Variant chr13-77903339-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 228342.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDNRB | NM_001122659.3 | c.618G>A | p.Trp206Ter | stop_gained | 3/7 | ENST00000646607.2 | |
EDNRB-AS1 | NR_103853.1 | n.1695-4353C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDNRB | ENST00000646607.2 | c.618G>A | p.Trp206Ter | stop_gained | 3/7 | NM_001122659.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250518Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135392
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460986Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726806
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GnomAD4 genome ? Cov.: 32
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Cov.:
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 09, 2015 | The p.Trp296X variant in EDNRB has not been previously reported in individuals w ith hearing loss or Waardenburg syndrome, and was absent from large population s tudies. This nonsense variant leads to a premature termination codon at position 296, which is predicted to lead to a truncated or absent protein. Loss of funct ion of the EDNRB gene is an established disease mechanism in autosomal recessive Waardenburg syndrome and has also been suggested to cause autosomal dominant Wa ardenburg syndrome based on reports from a small number of families (Pingault 20 10). In summary, this variant meets our criteria to be classified as pathogenic for Waardenburg syndrome in an autosomal recessive manner based on the predicted impact of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
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