rs2070591

Positions:

chr13-77918599-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001201397.2(EDNRB):c.245G>A(p.Arg82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,570,668 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 9 hom. )

Consequence

EDNRB
NM_001201397.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -0.415

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004188329).

BP6

Variant 13-77918599-C-T is Benign according to our data. Variant chr13-77918599-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225346.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, Benign=2}. Variant chr13-77918599-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000566 (86/152074) while in subpopulation EAS AF= 0.0101 (52/5134). AF 95% confidence interval is 0.00793. There are 1 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001122659.3 link	c.-26G>A		5_prime_UTR_variant	1/7	ENST00000646607.2	NP_001116131.1	P24530-1
EDNRB	NM_001201397.2 link	c.245G>A	p.Arg82Gln	missense_variant	2/8		NP_001188326.1	P24530-3A0A024R638
EDNRB	NM_000115.5 link	c.-26G>A		5_prime_UTR_variant	2/8		NP_000106.1	P24530-1
EDNRB	NM_003991.4 link	c.-26G>A		5_prime_UTR_variant	1/7		NP_003982.1	P24530-2A0A024R645

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2 link	c.-26G>A		5_prime_UTR_variant	1/7		NM_001122659.3	ENSP00000493527.1		P24530-1

Frequencies

GnomAD3 genomes

AF:

0.000566

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0101

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00101

AC:

202

AN:

199866

Hom.:

AF XY:

0.000970

AC XY:

106

AN XY:

109304

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000148

Gnomad EAS exome

AF:

0.00935

Gnomad SAS exome

AF:

0.000268

Gnomad FIN exome

AF:

0.00226

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.000836

GnomAD4 exome

AF:

0.000463

AC:

657

AN:

1418594

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

353

AN XY:

704782

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000128

Gnomad4 EAS exome

AF:

0.0107

Gnomad4 SAS exome

AF:

0.000176

Gnomad4 FIN exome

AF:

0.00188

Gnomad4 NFE exome

AF:

0.0000937

Gnomad4 OTH exome

AF:

0.000459

GnomAD4 genome

AF:

0.000566

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000740

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0101

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000609

Hom.:

Bravo

AF:

0.000450

ExAC

AF:

0.000974

AC:

118

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hirschsprung disease, susceptibility to, 2

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Waardenburg syndrome type 4A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 05, 2015

p.Arg82Gln in exon 2 of EDNRB: This variant is not expected to have clinical sig nificance because it has been identified in 1.2% (86/7046) of East Asian chromos omes including 1 homozygote by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs2070591). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2020

This variant is associated with the following publications: (PMID: 17011274, 18162831, 8852660, 21531202, 30098700) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.8

DANN

Uncertain

0.98

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.87

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.40

REVEL

Benign

0.28

Sift

Benign

0.12

Sift4G

Uncertain

0.055

Polyphen

0.0010

Vest4

0.036

MVP

0.56

MPC

0.52

ClinPred

0.061

GERP RS

-1.1

gMVP

0.066

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over