dbSNP rs104894389: EDNRB:p.Trp275* (chr13-77901185-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001122659.3(EDNRB):c.824G>A(p.Trp275*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EDNRB
NM_001122659.3 stop_gained

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 4.53

Publications

5 publications found

Variant links:

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]

EDNRB links:

EDNRB-AS1 (HGNC:49045): (EDNRB antisense RNA 1)

EDNRB-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122659.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDNRB	NM_001122659.3	MANE Select	c.824G>A	p.Trp275*	stop_gained	Exon 4 of 7	NP_001116131.1	P24530-1
EDNRB	NM_001201397.2		c.1094G>A	p.Trp365*	stop_gained	Exon 5 of 8	NP_001188326.1	P24530-3
EDNRB	NM_000115.5		c.824G>A	p.Trp275*	stop_gained	Exon 5 of 8	NP_000106.1	P24530-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDNRB	ENST00000646607.2	MANE Select	c.824G>A	p.Trp275*	stop_gained	Exon 4 of 7	ENSP00000493527.1	P24530-1
EDNRB	ENST00000377211.8	TSL:1	c.1094G>A	p.Trp365*	stop_gained	Exon 5 of 8	ENSP00000366416.4	P24530-3
EDNRB	ENST00000626030.1	TSL:1	c.824G>A	p.Trp275*	stop_gained	Exon 4 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725772

African (AFR)

AF:

0.00

AC:

AN:

33330

American (AMR)

AF:

0.00

AC:

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110212

Other (OTH)

AF:

0.00

AC:

AN:

60192

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:risk factor

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hirschsprung disease, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.97

PhyloP100

4.5

Vest4

0.92

GERP RS

5.5

Mutation Taster

=0/200

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over