Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_001122659.3(EDNRB):c.548C>G(p.Ala183Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

EDNRB
NM_001122659.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.60

Publications

12 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001122659.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.786

PP5

Variant 13-77903543-G-C is Pathogenic according to our data. Variant chr13-77903543-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 16634.Status of the report is no_assertion_criteria_provided, 0 stars.

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
EDNRB	NM_001122659.3	MANE Select	c.548C>G	p.Ala183Gly	missense	Exon 2 of 7	NP_001116131.1
EDNRB	NM_001201397.2		c.818C>G	p.Ala273Gly	missense	Exon 3 of 8	NP_001188326.1
EDNRB	NM_000115.5		c.548C>G	p.Ala183Gly	missense	Exon 3 of 8	NP_000106.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EDNRB	ENST00000646607.2	MANE Select	c.548C>G	p.Ala183Gly	missense	Exon 2 of 7	ENSP00000493527.1
EDNRB	ENST00000377211.8	TSL:1	c.818C>G	p.Ala273Gly	missense	Exon 3 of 8	ENSP00000366416.4
EDNRB	ENST00000626030.1	TSL:1	c.548C>G	p.Ala183Gly	missense	Exon 2 of 7	ENSP00000486202.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Waardenburg syndrome type 4A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.4

PhyloP100

9.6

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.64

Sift

Benign

0.035

Sift4G

Benign

0.11

Polyphen

0.022

Vest4

0.59

MutPred

0.77

Loss of ubiquitination at K182 (P = 0.1231)

MVP

0.76

MPC

0.57

ClinPred

0.97

GERP RS

4.8

PromoterAI

0.0054

Neutral

(source)

Varity_R

0.54

gMVP

0.66

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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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rs104894388

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over