dbSNP rs2070591: EDNRB:p.Arg82Gln (chr13-77918599-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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

Publications

8 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 Gene-Disease associations (from GenCC):

ABCD syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Waardenburg syndrome type 4A
Inheritance: SD, AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
Waardenburg syndrome type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Waardenburg-Shah syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hirschsprung disease, susceptibility to, 2
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

EDNRB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 225346.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR,Unknown,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001201397.2. 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.-26G>A		5_prime_UTR	Exon 1 of 7	NP_001116131.1	P24530-1
EDNRB	NM_001201397.2		c.245G>A	p.Arg82Gln	missense	Exon 2 of 8	NP_001188326.1	P24530-3
EDNRB	NM_000115.5		c.-26G>A		5_prime_UTR	Exon 2 of 8	NP_000106.1	P24530-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDNRB	ENST00000377211.8	TSL:1	c.245G>A	p.Arg82Gln	missense	Exon 2 of 8	ENSP00000366416.4	P24530-3
EDNRB	ENST00000646607.2	MANE Select	c.-26G>A		5_prime_UTR	Exon 1 of 7	ENSP00000493527.1	P24530-1
EDNRB	ENST00000626030.1	TSL:1	c.-26G>A		5_prime_UTR	Exon 1 of 7	ENSP00000486202.1	P24530-2

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

GnomAD2 exomes

AF:

0.00101

AC:

202

AN:

199866

AF XY:

0.000970

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 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

African (AFR)

AF:

0.00

AC:

AN:

31800

American (AMR)

AF:

0.00

AC:

AN:

36778

Ashkenazi Jewish (ASJ)

AF:

0.000128

AC:

AN:

23436

East Asian (EAS)

AF:

0.0107

AC:

423

AN:

39576

South Asian (SAS)

AF:

0.000176

AC:

AN:

79440

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

43572

Middle Eastern (MID)

AF:

0.000895

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.0000937

AC:

103

AN:

1099614

Other (OTH)

AF:

0.000459

AC:

AN:

58792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000566

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000740

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41478

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0101

AC:

AN:

5134

South Asian (SAS)

AF:

0.000208

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67978

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000706

Hom.:

Bravo

AF:

0.000450

ExAC

AF:

0.000974

AC:

118

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hirschsprung disease, susceptibility to, 2 (2)

not provided (1)

not specified (1)

Waardenburg syndrome type 4A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.8

(source)

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

PhyloP100

-0.41

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

PromoterAI

-0.031

Neutral

(source)

gMVP

0.066

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over